The impact of subthalamic deep brain stimulation on bradykinesia of proximal and distal upper limb muscles in Parkinson's disease.
To assess the differential effects of bilateral deep brain stimulation of the subthalamic nucleus on proximal and distal muscle groups of the upper limb in Parkinson's disease. Eight parkinsonian subjects with chronic bilateral stimulation of the subthalamic nucleus performed index finger tapping (differentially drawing upon distal arm muscles), horizontal pointing (differentially drawing upon proximal arm muscles) and a complex reach-to-grasp task with cubes of different sizes, which involved both proximal and distal arm muscles. An ultrasound based system was used for kinematic motion analysis. Subjects were investigated in two clinical conditions: on and off subthalamic nucleus stimulation. Clinical symptom severity was rated with the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscore. Stimulation of the subthalamic nucleus improved the UPDRS motor subscore (68 %). Bradykinesia of index finger tapping and horizontal pointing were equally improved by subthalamic nucleus stimulation. In contrast, in a complex reach-to-grasp task bradykinesia was differentially ameliorated for the grasp component. The data suggest that bilateral stimulation of the subthalamic nucleus improves bradykinesia of both distal and proximal muscles of the arm and hand in Parkinson's disease; however, dependent upon task complexity proximal and distal movement components may be affected differentially. Kinematic motion analysis is an efficient tool to objectively evaluate the beneficial effects of subthalamic nucleus stimulation on dexterity in Parkinson's disease.


Anatomy of the midline.
Described are the anatomy and topography of the midline structures particularly in relation to the surgical approaches. Furthermore measurements of the third ventricle and the various distances between surface areas of the brain and skull and different landmarks of the cerebral midline are presented.


Species richness disparity in tropical terrestrial herbaceous floras: Evolutionary insight from Collabieae (Orchidaceae).
Species richness is spatially heterogeneous even in the hyperdiverse tropical floras. The main cause of uneven species richness among the four tropical regions are hot debated. To date, higher net diversification rates and/or longer colonization time have been usually proposed to contribute to this pattern. However, there are few studies to clarify the species richness patterns in tropical terrestrial floras. The terrestrial tribe Collabieae (Orchidaceae) unevenly distributes in the tropical regions with a diverse and endemic center in Asia. Twenty-one genera 127 species of Collabieae and 26 DNA regions were used to reconstruct the phylogeny and infer the biogeographical processes. We compared the topologies, diversification rates and niche evolutionary rates of Collabieae and regional lineages on empirical samplings and different simulated samplings fractions respectively. Our results suggested that the Collabieae originated in Asia at the earliest Oligocene, and then independently spread to Africa, Central America, and Oceania since the Miocene via long-distance dispersal. These results based on empirical data and simulated data were similar. BAMM, GeoSSE and niche analyses inferred that the Asian lineages had higher net diversification and niche evolutionary rates than those of Oceanian and African lineages on the empirical and simulated analyses. Precipitation is the most important factor for Collabieae, and the Asian lineage has experienced more stable and humid climate, which may promote the higher net diversification rate. Besides, the longer colonization time may also be associated with the Asian lineages' diversity. These findings provided a better understanding of the regional diversity heterogeneity in tropical terrestrial herbaceous floras.


Effect of intraventricularly injected ricin on protein synthesis in rat brain.
Ricin, a protein from the seeds of Ricinus communis which inhibits protein synthesis by eukaryotic ribosomes, is highly toxic when injected intraventricularly to rats, the LD50 being 0.241 micrograms/rat at 72 hr and 0.084 micrograms/rat at 7 days. Poisoned animals showed signs of central depression; they did not die before 20 hr of intoxication. Incorporation of amino acids in vivo into brain total protein and into brain ribosomes was impaired, as was protein synthesis in vitro by microsomes isolated from the brain of poisoned rats.


[Williams and Beuren's syndrome with hypertension and associated renal abnormalities (author's transl)].
The authors presented a case of the Williams and Beuren's syndrome, special by the existence of aorta coarctation, high blood pressure, nephrotic syndrome and renal dysplasia. The Williams-Beuren's syndrome is characterised by the association of facial anomalies, mental retardation and supra-valvular aortic stenosis. The case presented in this study demonstrates: -- the symptomatic diversity of the Williams and Beuren's syndrome; -- and the relationship of this syndrome and severe idiopathic hypercalcemia of the infant. The etiopathogenesis is also discussed.


Contribution of αβ T cells to macrophage polarization and MSC recruitment and proliferation on titanium implants.
Physiochemical cues like topography and wettability can impact the inflammatory response and tissue integration after biomaterial implantation. T cells are essential for immunomodulation of innate immune cells and play an important role in the host response to biomaterial implantation. This study aimed to understand how CD4+ and CD8+ T cell subsets, members of the αβ T cell family, polarize in response to smooth, rough, or rough-hydrophilic titanium (Ti) implants and whether their presence modulates immune cell crosstalk and mesenchymal stem cell (MSC) recruitment following biomaterial implantation. Post-implantation in mice, we found that CD4+ and CD8+ T cell subsets polarized differentially in response to modified Ti surfaces. Additionally, mice lacking αβ T cells had significantly more pro-inflammatory macrophages, fewer anti-inflammatory macrophages, and reduced MSC recruitment in response to modified Ti post-implantation than αβ T cell -competent mice. Our results demonstrate that T cell activation plays a significant role during the inflammatory response to implanted biomaterials, contributing to macrophage polarization and MSC recruitment and proliferation, and the absence of αβ T cells compromises new bone formation at the implantation site. STATEMENT OF SIGNIFICANCE: T cells are essential for immunomodulation and play an important role in the host response to biomaterial implantation. Our results demonstrate that T cells actively participate during the inflammatory response to implanted biomaterials, controlling macrophage phenotype and recruitment of MSCs to the implantation site.


The effect of adrenaline on the electrogenic Na+ pump in cardiac muscle cells.
Electrogenic Na+ pump currents during K+-activated hyperpolarizations of bullfrog atrium muscle fibres are increased by adrenaline. The log dose-response relation between these currents and activating K+ concentrations is expressed by a sigmoidal curve, which is shifted in parallel to the left by adrenaline. It is suggested that adrenaline increases the rate of Na+ extrusion without increasing the Na/K coupling ratio and total number of pumping sites.


Flavin-nicotinamide biscoenzymes: models for the interaction between NADH (NADPH) and flavin in flavoenzymes. Reaction rates and physicochemical properties of intermediate species.
1. Flavin-nicotinamide biscoenzymes covalently linked by two, three or four methylene groups through positions N(10) of the flavin (Fl) and (N1) of the nicontinamide (Nic) form long-wavelength-absorbing, intramolecular complexes when the flavin part of the molecule is reduced specifically. The energy of the long-wavelength transition is minimal and its intensity maximal for (see journal for formula). 2. The increasing proximity of the positively charged nicotinamide lowers the pK-value of dihydroflavin deprotonation up to 1.7 units and the flavin oxidation-reduction potential becomes more positive up to 116 mV. 3. Specific reduction of the nicotinamide part of the biscoenzymes yields transient, long-wavelength-absorbing complexes. The energy of the long-wavelength transition is minimal and its intensity maximal for the complex (see journal for formula). 4. The rate of intramolecular flavin-dependent dihydronicotinamide dehydrogenation is highest for (see journal for formula), about 3 times slower for (see journal for formula) and 100 times slower for (see journal for formula). 5. The results obtained in this study are consistent with a reaction mechanism that involves formation of a charge transfer complex between reduced nicotinamide and oxidized flavin and rate-limiting heterolytic breakdown into products.


Risk factors associated with colistin resistance in carbapenemase-producing Enterobacterales: a multicenter study from a low-income country.
The aim of this study was to assess the risk factors for colistin-resistant carbapenemase-producing Enterobacterales (CR-CPE), and describe the mortality associated with this organism, in a low-income country. A descriptive, observational, and prospective multicenter study was carried out in Guayaquil, Ecuador. All patients with carbapenem-resistant Enterobacterales admitted between December 2021 and May 2022 were enrolled. Infection definitions were established according to the Centers for Disease Control and Prevention (CDC) protocols. The presence of carbapenemase-producing Enterobacterales was confirmed with a multiplex PCR for blaKPC, blaNDM, blaOXA-48, blaVIM, and blaIMP genes. MCR-1 production was studied molecularly, and MLST assays were carried out. Out of 114 patients enrolled in the study, 32 (28.07%) had at least one positive sample for CR-CPE. Klebsiella pneumoniae ST512-KPC-3 was the most frequent microorganism isolated. Parenteral feeding, β-lactamase inhibitor use, recent hemodialysis, and renal failure were all considered independent risk factors for carrying CR-CPE. A mortality of 41.22% was detected, but we could not find any difference between colistin-resistant and colistin-susceptible CPE. MCR-1 production was not detected in any of the isolates studied. A significant burden for CR-CPE was found in a South American country that was mainly caused by the high-risk clone K. pneumoniae ST512-KPC-3 and not mediated by mcr-1 production. Its acquisition involved parenteral feeding, β-lactamase inhibitor use, recent hemodialysis, and renal failure as independent risk factors, demonstrating the critical need for infection prevention and stewardship programs to avoid dissemination to other countries in the region.


Uptake and esterification of arachidonic acid by trophozoites of Giardia lamblia.
Although trophozoites of Giardia lamblia have not been demonstrated to possess the capacity for synthesis of phospholipids, these protozoan parasites would be exposed to fatty acids within the human small intestine. We have evaluated the metabolic incorporation of arachidonic and palmitic acids by Giardia trophozoites. Trophozoites (2.25 X 10(6)) were incubated with 12 nM [3H]fatty acid for up to 60 min. Uptake of [3H]arachidonate by trophozoites was rapid, increasing from 37% at 1 min to 65% at 10 min. Uptake of palmitate was rapid but less extensive. In contrast to palmitate, almost all of the trophozoite-associated [3H]arachidonate was esterified into phospholipids and neutral lipids. By 1 and 60 min 37% and 82% of [3H]arachidonate, respectively, were incorporated into phospholipids, including phosphatidylinositol and phosphatidylcholine. Peak incorporation of [3H]arachidonate into phosphatidylcholine (30 mmol [3H]fatty acid (mol phospholipid)-1) occurred at 60 min; whereas incorporation into the pool of phosphatidylinositol, which accounted for only 4% of trophozoite phospholipid, was maximal at 10 min (190 mmol [3H]fatty acid (mol phospholipid)-1) and declined significantly thereafter as arachidonic acid was released from phosphatidylinositol. Therefore, Giardia trophozoites not only utilize exogenous fatty acids in the formation of glycerolipids but also preferentially incorporate arachidonic acid into a metabolically active pool of phosphatidylinositol.


'He or she maybe doesn't know there is such a thing as a review': A qualitative investigation exploring barriers and facilitators to accessing medication reviews from the perspective of people from ethnic minority communities.
Regular reviews of medications, including prescription reviews and adherence reviews, are vital to support pharmacological effectiveness and optimize health outcomes for patients. Despite being more likely to report a long-term illness that requires medication when compared to their white counterparts, individuals from ethnic minority communities are less likely to engage with regular medication reviews, with inequalities negatively affecting their access. It is important to understand what barriers may exist that impact the access of those from ethnic minority communities and to identify measures that may act to facilitate improved service accessibility for these groups. Semi-structured interviews were conducted between June and August 2021 using the following formats as permitted by governmental COVID-19 restrictions: in person, over the telephone or via video call. Perspectives on service accessibility and any associated barriers and facilitators were discussed. Interviews were audio-recorded and transcribed verbatim. Reflexive thematic analysis enabled the development of themes. QSR NVivo (Version 12) facilitated data management. Ethical approval was obtained from the Health Research Authority (ref: 21/HRA/1426). In total 20 participants from ethnic minority communities were interviewed; these participants included 16 UK citizens, 2 refugees and 2 asylum seekers, and represented a total of 5 different ethnic groups. Three themes were developed from the data regarding the perceived barriers and facilitators affecting access to medication reviews and identified approaches to improve the accessibility of such services for ethnic minority patients. These centred on (1) building knowledge and understanding about medication reviews; (2) delivering medication review services; and (3) appreciating the lived experience of patients. The results of this study have important implications for addressing inequalities that affect ethnic minority communities. Involving patients and practitioners to work collaboratively in coproduction approaches could enable better design, implementation and delivery of accessible medication review services that are culturally competent. The National Institute for Health Research Applied Research Collaboration and Patient and Public Involvement and Engagement group at Newcastle University supported the study design and conceptualization. Seven patient champions inputted to ensure that the research was conducted, and the findings were reported, with cultural sensitivity.


The health of adolescents: beliefs and behaviour.
Adolescence is a period of transition from childhood to adulthood in which interlocking changes in the body, mind and social relationship take place. Healthy development depends on both a propitious environment and the action of adolescents themselves. A stable family, peace, material conditions for physical health, and educational, social and vocational opportunities with a chance to make use of them before marriage, are necessary environment conditions. However, within this context the adolescent must experiment with new behaviours and relationships inevitably courting some risks. Adolescent health is especially linked to behaviour. If the environment is inadequate or dangerous and the adolescent lacks self-esteem, behaviours dangerous to health are more likely to occur. These include: precocious and unprotected sexual behaviour sometimes resulting in too early or unwanted pregnancy and sexually transmitted diseases; the use of tobacco, alcohol and other drugs; injuries arising accidentally from risk taking behaviours especially when combined with alcohol or drugs; intentional injury whether self-inflicted or inflicted by others; and poor eating and habits of hygiene leading to obesity, or emaciation, acne and poor teeth and gums. Adolescent behaviour is often governed by their beliefs about what others think. Two way communication in a trusting atmosphere will reduce myths and misinformation and encourage healthy behaviour. The promotion of health, the prevention of problems, and their treatment and rehabilitation when they arise can best be accomplished with the active co-operation of young people.


Effect of successive single-gestation pregnancies on the course of maternal human immunodeficiency virus disease and perinatal transmission.
This study was undertaken to examine the effect of successive pregnancies over a 3-year period on the course of maternal human immunodeficiency virus (HIV) infection and the rate of perinatal transmission of HIV. A retrospective analysis of 32 pregnancies in 14 known HIV-infected women vs. a matched control group of HIV-infected women who had been pregnant only once was done. The multiple-pregnancy group was similar to the single-pregnancy group for age, race, duration of known HIV infection, initial CD(4) count, and date of first pregnancy. The delivery data were similar as well. The CD(4) counts in the multiple-pregnancy group fell from 595 to 460, while counts in the single-pregnancy group fell comparably from 669 to 638, both over 37 months (P = 0.1476). Five of 5 second-born infants of known serostatus vs. 8 of 21 first-born infants were HIV-infected (P < 0.05). Successive pregnancies do not alter the course of HIV infection in asymptomatic women followed up to 3 years. The infants of second pregnancies of known HIV-infected women may be at higher risk for perinatal transmission.


Localization and direct quantitation of 3H-labeled proteins and RNAs in slab gels by a new detection system.
The distribution patterns of 3H-labeled proteins and RNAs in dehydrated polyacrylamide and agarose gels have been recorded with a newly developed instrument: the Linear Analyzer which has a position-sensitive detector that counts a whole gel lane simultaneously. The high sensitivity makes the Linear Analyzer a suitable instrument for direct quantitation of tritium labeled macromolecules in gels without pretreatment by impregnating reagents. The very low detection limit of the Linear Analyzer reduces substantially the time of evaluation in comparison to the relatively long exposure times needed in fluorography. The resolution of radioactivity profiles monitored by the Linear Analyzer reaches the quality attained by fluorography.


Pretreatment of corn stover by soaking in aqueous ammonia at moderate temperatures.
Soaking in aqueous ammonia at moderate temperatures was investigated as a method of pretreatment for enzymatic hydrolysis as well as simultaneous saccharification and cofermentation (SSCF) of corn stover. The method involves batch treatment of the feedstock with aqueous ammonia (15-30 wt%) at 40-90 degrees C for 6-24 h. The optimum treatment conditions were found to be 15 wt% of NH(3), 60 degrees C, 1:6 of solid-to-liquid ratio, and 12 h of treatment time. The treated corn stover retained 100% glucan and 85% of xylan, but removed 62% of lignin. The enzymatic digestibility of the glucan content increased from 17 to 85% with 15 FPU/g-glucan enzyme loading, whereas the digestibility of the xylan content increased to 78%. The treated corn stover was also subjected to SSCF test using Spezyme-CP and recombinant Escherichia coli (KO11). The SSCF of the soaking in aqueous ammonia treated corn stover resulted in an ethanol concentration of 19.2 g/L from 3% (w/v) glucan loading, which corresponds to 77% of the maximum theoretical yield based on glucan and xylan.


Long-term outcomes of choledochoduodenostomy for choledocholithiasis: increased incidence of postoperative cholangitis after total or distal gastrectomy.
Choledochoduodenostomy (CDD) is performed to treat choledocholithiasis (CDL) cases where endoscopic stone removal is difficult. Recognizing CDD characteristics is important for CDL treatment planning. A total of 116 patients, including 33 patients ≥ 80 years old (29 with previous total gastrectomy, 19 with previous distal gastrectomy, 20 with built-up stones, 19 with periampullary diverticulum, 10 with confluence stones, 8 with repetitive recurrent stones, 4 with hard stones, 3 with endoscopic retrograde cholangiography [ERC] not available due to lack of cooperation, 2 with a history of pancreatitis post-ERC, and 2 in whom ERC could not be performed due to a disturbed anatomy) underwent CDD for CDL. Postoperative complications and long-term outcomes were evaluated. The in-hospital mortality rate was 0%. The morbidity (grade ≥ IIIA according to the Clavien-Dindo classification) rates in the elderly (≥ 80 years old) and non-elderly (51-79 years old) patients were 3.0% (1/33) and 2.4% (2/83), respectively (p = 0.85). Long-term complications included cholangitis in eight (7%) patients, of which three cases were repetitive and seven had an operative history of total or distal gastrectomy. The incidence of postoperative cholangitis after total or distal gastrectomy was 15% (7/48), which was significantly higher than that involving other causes (1.5%, 1/68; p < 0.01). Two patients with cholangitis after total gastrectomy experienced early recurrence of lithiasis at 2 and 9 months after surgery. CDD is safe, even in elderly patients. However, a history of total gastrectomy or distal gastrectomy may increase the incidence of postoperative cholangitis.


In vivo muscle magnetic resonance spectroscopy in a family with mitochondrial cytopathy: a defect in fat metabolism.
In vivo proton and phosphorus magnetic resonance spectroscopy (MRS) studies were performed at 1.5 T on two patients (siblings) diagnosed as having a mitochondrial cytopathy. The clinical diagnosis was based on a complete battery of biochemical tests, electron microscopy and modified Gomori trichrome stain studies of muscle. Proton spectra from the gastrocnemius muscle were recorded using the stimulated echo acquisition mode (STEAM) and the phosphorus spectra were obtained using the depth-resolved surface coil spectroscopy (DRESS) sequence. Proton resonances from neutral fats in the patients were found to be strikingly weak compared to normals. The ratios [PCr]/[ATP] and [PCr]/[Pi] and the pH values, as inferred from the phosphorus MRS, were found to be marginally decreased compared to normals. These studies indicate defective fatty acid metabolism in these two patients. It is, however, not known whether the abnormal mitochondrial ultrastructure represents a primary abnormality or secondary to defective fatty acid metabolism.


Generation of the vesicular stomatitis virus nucleoprotein cytotoxic T lymphocyte epitope requires proteasome-dependent and -independent proteolytic activities.
The proteasome is involved in the generation of most of the MHC class I antigenic epitopes. However, it is not known if the proteasome generates the exact cytotoxic T lymphocyte (CTL) epitope or only epitope precursors which require further modification by additional proteases. Digestion of the extended vesicular stomatitis virus nucleoprotein epitope 52-59 (RGYVYQGL) by the 20S proteasome in vitro shows that the proteasome is capable of generating the correct C terminus but not the exact N terminus of the CTL epitope. This finding suggests that proteolytic activity in addition to the proteasome is required for generation of the CTL epitope. By using the proteasome inhibitor lactacystin we were able to confirm this finding in vivo. Lactacystin prevented the processing of N- and C-terminally extended epitopes, whereas the processing of only N-terminally extended epitopes was unaffected. Thus, the proteasome is necessary and sufficient for the generation of the exact C terminus of this CTL epitope, whereas the exact N terminus seems to be generated by a different protease.


Flexible topographical design of light-emitting diodes realizing electrically controllable multi-wavelength spectra.
Multi-wavelength visible light emitters play a crucial role in current solid-state lighting. Although they can be realized by combining semiconductor light-emitting diodes (LEDs) and phosphors or by assembling multiple LED chips with different wavelengths, these design approaches suffer from phosphor-related issues or complex assembly processes. These challenges are significant drawbacks for emerging applications such as visible light communication and micro-LED displays. Herein we present a platform for tailored emission wavelength integration on a single chip utilizing epitaxial growth on flexibly-designed three-dimensional topographies. This approach spontaneously arranges the local emission wavelengths of InGaN-based LED structures through the local In composition variations. As a result, we demonstrate monolithic integration of three different emission colors (violet, blue, and green) on a single chip. Furthermore, we achieve flexible spectral control via independent electrical control of each component. Our integration scheme opens the possibility for tailored spectral control in an arbitrary spectral range through monolithic multi-wavelength LEDs.


Laboratory pitfalls that contribute to embrasure clasp failure.
Use of an embrasure clasp demands attention to proper clinical preparation and to laboratory procedures as well. This article outlined pitfalls that occur in the laboratory, and appropriate solutions were offered.


The presbyopic add. III. Influence of the distance refractive type.
The possibility of the distance refractive type-emmetropia, hypermetropia or myopia-influencing the magnitude and rate of change of the presbyopic add does not seem to have received systematic consideration. To address this possibility a further series of transverse clinical data on the progression of the presbyopic add is presented. Analysis of these data reveals the influence of the distance refractive type on the presbyopic progression. Hypermetropes appear to show a two-phase rise in add requirement whereas emmetropes follow a linear and myopes a curvilinear path over the four decades between 41 and 80 years of age. Nevertheless the magnitude of the binocular add requirement at a given age for each of the three refractive types is very similar and all three classes maintain an increasing requirement with advancing age.


Harvesting freshwater algae with tannins from the bark of forest species: Comparison of methods and pelletization of the biomass obtained.
Toxic cyanobacteria growth rates have increased in recent decades due to climate change and human activities. Microalgae, with their ability to produce a large amount of biomass, are considered as a source of energy that can be used to produce biofuels. The aim of this study is to test four different microalgae harvesting methods (sedimentation, coagulation-flocculation, pH variation, and centrifugation) in order to find which is best suited to the A Baxe reservoir, which has been suffering from cyanobacterial blooms in recent years. Centrifugation proved the most efficient method (85.74%-1790 RCF), but it can induce cell rupture. Natural sedimentation and pH variation obtained similar results at 49.36% and 49.02% respectively. Although all four methods have advantages, our results reveal that coagulation-flocculation, using 10 mg/L of Pinus pinaster, results in a removal efficiency of 68.10%, making it the most suitable method, though with 20 mg/L the performance was lower (66.03%). To minimise environmental waste, the microalgae removed were then transformed into pellets to be used as biofuel, with a higher heating value (HHV) of 21,196.96 ± 1602.33 kJ/kg. The pellets obtained from the microalgae residue did not meet all the requirements for use as biofuels, but microalgae biomass could be mixed with other sources and therefore looks like a promising option for the future.


Invasiveness of human glioma cell lines in vitro: relation to tumorigenicity in athymic mice.
Five established cell lines derived from human anaplastic astrocytomas or glioblastoma multiforme were tested for invasiveness into precultured chick heart fragments in vitro. Four of the cell lines (U118 MG, D54 MG, U373 MG and A172) were strongly invasive into the heart tissue. A fifth cell line, U251 MG sp, which was only tumorigenic at doses of greater than 1 X 10(8) cells in athymic mice, was non-invasive in vitro. One line, A172, was invasive but not tumorigenic in athymic mice, although a related invasive subline, D54 MG, at later passage levels was tumorigenic even at low cell doses. Invasion of the glioma cells was characterized by progressive and irreversible replacement of the precultured chick heart tissue. Both by light and transmission electron microscopy, a similar pattern of invasion was observed as earlier found with experimental rat glioma cells in the same system. Some human cell lines established from human gliomas retain invasive properties after a prolonged culture period in vitro.


Dual-origin plasmid vectors whose origin of replication is controlled by the coliphage lambda promoter pL.
The insertion of an XhoI linker 30 bp from the 5' end of the RNA II primer for ColE1 plasmid replication has allowed us to replace the natural RNA II promoter by other controllable promoters, in particular lambda pL. Manipulation of this modified origin was facilitated by constructing dual-origin plasmids, stable maintenance being directed by the pSC101 origin. Experiments showed that such dual-origin plasmids could be stably maintained at approximately four copies per chromosome at 30 degrees C and readily amplified by thermal induction of strains carrying a thermolabile lambda repressor. The use of such plasmids for the construction of stable, amplifiable expression vectors is discussed.


Development and Validation of a Nomogram for Predicting Death within 2 days After Intracerebral Hemorrhage.
This study aimed to establish and verify a model for predicting death within 2 days after spontaneous cerebral hemorrhage based on the patient's characteristics at the time of admission. During 2015-2017, the records of a cohort of 397 patients with clinically diagnosed cerebral hemorrhage were collected for model development. Minimum absolute contraction and the selection operator (lasso) regression model were used to determine factors that most consistently and correctly predicted death after cerebral hemorrhage. Discrimination and calibration were used to evaluate the performance of the resulting nomogram. After internal validation, the nomogram was further assessed during 2017-2018 using a different cohort of 200 consecutive subjects. The nomogram included four predictors from the lasso regression analysis: Glasgow Coma Scale, hematoma location, hematoma volume, and primary intraventricular hemorrhage. The nomogram showed good discrimination and good calibration for both training and verification cohorts. Decision curve analysis showed that the prediction nomogram was clinically useful. This prediction model can be used for early, simple, and accurate prediction of early death following cerebral hemorrhage.


Healthcare spending among community-dwelling adults with schizophrenia.
Although expenditures for schizophrenia have been documented previously, direct medical expenses have not been updated to reflect the most recent national data available. To identify current direct medical expenditures for schizophrenia and comorbidities among community-dwelling adults in the United States. Cross-sectional. Nationally representative data from the 2001 and 2002 Medical Expenditure Panel Surveys were analyzed to identify community-dwelling adults, aged 20 years, who incurred expenses for selected comorbidities. Annual direct medical spending estimates by site of service and payer source were produced using the average of these 2-year data. Mean and median per-person comorbidity costs among patients with schizophrenia expenses were determined for the following conditions: diabetes, hypertension, heart disease, and dyslipidemia. Five hundred seventy-one thousand community-dwelling adults incurred USD 2.13 billion per year in direct medical expenses for schizophrenia in 2001-2002; mean and median yearly per-patient expenses were USD 3726 and USD 1748, respectively. Inpatient care accounted for 13% of expenditures, while ambulatory care and prescription drugs accounted for 75%. Medicaid incurred USD 1 billion spent on schizophrenia treatment. Mean per-person spending for schizophrenia patients with comorbidities ranged from USD 3913 per year for those with comorbid hypertension to USD 5618 per year for those with comorbid dyslipidemia. Mean annual total healthcare expenditures for patients with schizophrenia ranged from USD 5990 for those with no comorbid conditions to USD 12 292 for those with comorbid hypertension. The majority of schizophrenia expenses incurred by patients living in the community occur in an outpatient setting and not in the hospital. Medicaid is the primary payer source for this condition. Among adults with schizophrenia, the costs of comorbidities vary by condition, but are associated with increased expenditures.


Starch biosynthesis: further evidence against the primer nonreducing-end mechanism and evidence for the reducing-end two-site insertion mechanism.
Two reactions were studied with three varieties of starch granules from maize, wheat, and rice. In Reaction-I, the granules were reacted with 1 mM ADP-[(14)C]Glc and in Reaction-II, a portion of the granules from Reaction-I was reacted with 1 mM ADP-Glc. The starch granules were solubilized and reacted with the exo-acting glucoamylase and beta-amylase to an extent of 50% or less of the (14)C-label. The amounts of (14)C-labeled products from glucoamylase and beta-amylase were nearly equal for Reaction-I and Reaction-II. If the addition had been to the nonreducing ends of primers, Reaction-II would not have given any labeled products from the hydrolysis of glucoamylase and beta-amylase. These results indicate that the elongation of the starch chain is the addition of D-glucose to the reducing end by a de novo two-site insertion mechanism and not by the addition of D-glucose to the nonreducing end of a primer. This is in conformity with previous results in which starch granules were pulsed with ADP-[(14)C]Glc and chased with nonlabeled ADP-Glc, giving (14)C-labeled D-glucitol from the pulsed starch and a significant decrease in (14)C-labeled D-glucitol from the chased starch on reducing with NaBH(4) and hydrolyzing with glucoamylase [Carbohydr. Res.2002, 337, 1015-1022]. It also is in conformity with the inhibition of starch synthesis that occurs when putative primers are added to starch granule-ADP-Glc digests, indicating that the elongation is not by the nonreducing-end primer mechanism [Carbohydr. Res.2005, 340, 245-255].


The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway.
In autoimmune hepatitis (AIH), liver-damaging CD4 T cell responses are associated with defective CD4(pos) CD25(pos) regulatory T cells (T-regs). Galectin-9 (Gal9), a β-galactosidase-binding protein expressed by T-regs, is key to their function, inhibiting T helper 1 immune responses by binding T cell immunoglobulin and mucin domain 3 (Tim-3) on CD4 effector cells. We investigated whether impaired immunoregulation in AIH results from reduced expression of Gal9 in T-regs and/or Tim-3 on CD4 effector cells. Circulating Gal9(pos) CD4(pos) CD25(pos) and Tim-3(pos) CD4(pos) CD25(neg) T cell phenotype was assessed by flow cytometry in 75 AIH patients. To evaluate whether Tim-3 expression renders CD4(pos) CD25(neg) T cells amenable to T-reg control, purified CD4(pos) CD25(neg) Tim-3(pos) (Tim-3(pos)) and CD4(pos) CD25(neg) Tim-3(neg) (Tim-3(neg)) cells were cocultured with T-regs. To determine whether Gal9 expression is essential to function, T-regs were treated with small interfering RNA (siRNA) to repress Gal-9 translation; T-reg suppressor function was assessed by proliferation. In AIH, Tim-3(pos) cells within CD4(pos) CD25(neg) cells and their T-bet(pos) and RORC(pos) subsets were fewer and contained higher numbers of interferon-γ (IFNγ)(pos) and interleukin (IL)-17(pos) cells than healthy subjects (HS). In AIH and HS, Tim-3(pos) cells proliferated less vigorously and were more susceptible to T-reg control than Tim-3(neg) cells. In AIH, Gal9(pos) T-regs were fewer and contained less FOXP3(pos), IL-10(pos), and transforming growth factor β(pos) and more IFNγ(pos) and IL-17(pos) cells than HS. siRNA treatment of Gal-9(pos) T-regs drastically reduced T-reg ability to suppress CD4(pos) CD25(neg) and Tim-3(pos) cell proliferation in AIH and HS. Tim-3(pos) cell percentage correlated inversely with aminotransferase and CD25(neg) T-bet(pos) cell values. Reduced levels of Tim-3 on CD4(pos) CD25(neg) effector cells and of Gal9 in T-regs contribute to impaired immunoregulation in AIH by rendering effector cells less prone to T-reg control and T-regs less capable of suppressing.


Stimulation of dense tubular Ca2+ uptake in human platelets by cAMP.
Elevation of intracellular cAMP is shown to increase the rate (V) and maximal extent of Ca2+ uptake by the dense tubules in intact human platelets. Elevation of [cAMP] was accomplished by preincubation with the adenylate cyclase activator forskolin or with dibutyryl-cAMP (Bt2-cAMP). The free concentration of Ca2+ in the dense tubular lumen ([Ca2+]dt) was monitored using the fluorescence of chlorotetracycline (CTC) according to protocols developed in this laboratory. The free cytoplasmic Ca2+ concentration ([Ca2+]cyt) was monitored in parallel experiments with quin2. Both [Ca2+]cyt and [Ca2+]dt were analyzed in terms of competition between pump and leak mechanisms in the plasma membrane (PM) and dense tubular membrane (DT). When platelets are incubated in media with approx. 1 microM external Ca2+, [Ca2+]cyt is approx. 50 nM and [Ca2+]dt is very low. When 2 mM external Ca2+ is added, [Ca2+]cyt rises to approx. 100 nM and the process of dense tubular Ca2+ uptake can be resolved. Forskolin (10 microM) and Bt2-cAMP increase the rate of dense tubular Ca2+ uptake (V) to 2.1 +/- 0.60 and 1.70 +/- 40 times control values (respectively). The agents also increase the final [Ca2+]dt to 1.70 +/- 0.21 and 1.72 +/- 0.60 times control values (respectively). Titrations with ionomycin (Iono) showed that the increase was due to an increase in the Vm of the dense tubular Ca2+ pump. With [Iono] = 500 nM, [Ca2+]cyt was raised to greater than or equal to 1.0 microM and Vm of the dense tubular pump was elicited. (At [Iono] = 1.0 microM, the final [Ca2+]dt values were degraded 15% due to shunting of Ca2+ uptake.) Analysis showed that forskolin (10 microM) and Bt2-cAMP (1 mM) increase the Vm by a factors of 1.56 +/- 40 and 1.56 +/- 40, respectively. Analysis showed that neither agent changed the Km of the pump significantly from its control value of 180 nM. Neither agent changed the rate constant for passive leakage of Ca2+ across the DT membrane (1.7 min-1).


Detection of thermal shift in cellular Keap1 by protein-protein interaction inhibitors using immunoblot- and fluorescence microplate-based assays.
Pharmacologic inhibition of the protein-protein interaction (PPI) interface of the Keap1:Nrf2 complex, which leads to Nrf2 activation and cytoprotective gene expression, offers a promising strategy for disease prevention and treatment. To facilitate identification and validation of small-molecule Keap1:Nrf2 PPI inhibitors in the cellular environment in a low- and medium-throughput manner, we detail two adapted cellular thermal shift assay (CETSA) protocols, Keap1-CETSA, an immunoblotting-based methodology for detecting endogenous Keap1, and Keap1-Glow CETSA, a microtiter plate assay of overexpressed fluorescently-tagged Keap1. For an example of the use and execution of this protocol, please refer to Dayalan Naidu et al. (2021).


Chemical manipulation of plant water use.
Agricultural productivity is dictated by water availability and consequently drought is the major source of crop losses worldwide. The phytohormone abscisic acid (ABA) is elevated in response to water deficit and modulates drought tolerance by reducing water consumption and inducing other drought-protective responses. The recent identification of ABA receptors, elucidation of their structures and understanding of the core ABA signaling network has created new opportunities for agrochemical development. An unusually large gene family encodes ABA receptors and, until recently, it was unclear if selective or pan-agonists would be necessary for modulating water use. The recent identification of the selective agonist quinabactin has resolved this issue and defined Pyrabactin Resistance 1 (PYR1) and its close relatives as key targets for water use control. This review provides an overview of the structure and function of ABA receptors, progress in the development of synthetic agonists, and the use of orthogonal receptors to enable agrochemical control in transgenic plants.


The effect of supine and lateral positions on intra-arterial pressure in hypertensive pregnancies.
The effect of posture of blood pressure remains controversial, perhaps due to the subjective nature of indirect blood pressure measurements and the disturbing influence of environmental impulses at the time of measurement. In this study intra-arterial blood pressure was recorded directly in seven toxemic gravid women in an environment with a low impulse level. There were short-term fluctuations of up to 25 mm. systolic and 15 mm. diastolic. The effect of changes in position on blood pressure was not constant and the differences were small. The effect on blood pressure of changing the environment by talking to the subject was impressive and the difference was more than twice the largest posture-induced difference.


Transient unilateral ophthalmoplegia without papilledema in a child with intracranial hypertension.
Intracranial hypertension is usually presented with papilledema and headache. Complete ophthalmoplegia without papilledema is a very rare finding of intracranial hypertension in children. A 5-year-old male patient with unilateral ophthalmoplegia due to increased intracranial pressure is presented. The fundoscopic examination and the magnetic resonance imaging of the brain were normal. He underwent lumboperitoneal shunt insertion for intracranial hypertension and the ophthalmoplegia was resolved one month later. Complete ophthalmoplegia without papilledema may occur following intracranial hypertension. Prompt and accurate diagnosis should be done and appropriate treatment to reduce the pressure should be performed to save the life of the children.


Neuromuscular hamartoma arising in the brachial plexus.
We report a case brachial plexus neuromuscular hamartoma (choristoma) in a 28-year-old man who complained of numbness of the left hand and forearm for several years. MRI revealed a circumscribed, rounded mass in the left brachial plexus. The patient is well 2 years after surgery, with no neurological deficit.


Improving bias and coverage in instrumental variable analysis with weak instruments for continuous and binary outcomes.
Causal estimates can be obtained by instrumental variable analysis using a two-stage method. However, these can be biased when the instruments are weak. We introduce a Bayesian method, which adjusts for the first-stage residuals in the second-stage regression and has much improved bias and coverage properties. In the continuous outcome case, this adjustment reduces median bias from weak instruments to close to zero. In the binary outcome case, bias from weak instruments is reduced and the estimand is changed from a marginal population-based effect to a conditional effect. The lack of distributional assumptions on the posterior distribution of the causal effect gives a better summary of uncertainty and more accurate coverage levels than methods that rely on the asymptotic distribution of the causal estimate. We discuss these properties in the context of Mendelian randomization.


Left and right ventricular adaptation assessed by Doppler tissue echocardiography in athletes.
Changes induced by intensive training in the morphology and kinetics of both ventricles in athletes (soccer players) were assessed by 2-dimensional echocardiography and Doppler tissue echocardiography (DTE). DTE has yet to find widespread application in sports medicine, and the right ventricle (RV) is often neglected in the examination of athletes. DTE-determined velocities were measured along the short and long axis in the left ventricle (LV) and over the long axis in the RV. Wall displacements (systolic shortenings and diastolic elongations) were computed at each site as time-velocity integrals. Normalized velocities and excursions were calculated with reference to the long and short diastolic dimensions. A total of 20 athletes and 15 age- and sex-matched control subjects were enrolled in the study. All participants underwent history screening, physical examination, electrocardiogram, and blood analysis. The athletes had significantly greater RV long-axis dimension and LV short-axis dimension than control subjects. LV ejection fraction was similar in the 2 groups. In athletes, peak systolic velocities were significantly increased along the LV short axis and the RV long axis. Early diastolic velocities were significantly increased for the LV short axis and nonsignificantly increased at all other sites. The ratio of these peak velocities to the proper diastolic dimension (fractional or normalized velocities) did not significantly differ between the groups. Time-velocity integrals (ie, wall tissue displacements) were increased in all directions examined in both ventricles, both in systole and early diastole. However, normalized or percent shortenings and elongations were similar in athletes and control subjects. These data suggest that an increase in RV and LV cavity size is associated with higher DTE-reported velocities in athletes. These higher velocities correspond to greater excursions of the muscle segments involved. Normalized velocities and excursions, however, indicate an unchanged fractional shortening, so that contractility has to be considered unaffected in these athletes. We suggest that DTE is instructive in unveiling functional adaptations of the heart in athletes, but questions of data interpretation have to be settled. For example, one should be cautious in comparing absolute velocities between chambers of different size. Nonnormalized velocities may be an objectionable index in the presence of cardiac enlargement.


Prevalence of cognitive dysfunction and its risk factors in children with chronic kidney disease in a developing country.
Chronic kidney disease (CKD) is associated with cognitive dysfunction. Cognitive function in children with CKD residing in developing countries has not been previously reported. This cross-sectional study included children aged 6-18 years with CKD stages 2-5D and kidney transplant. Cognitive function was assessed by WISC-V for children from 6-16 years of age. In adolescents 17-18 years of age, WAIS-III was used. Factors associated with cognitive dysfunction were identified using multivariable regression analysis. Thirty-seven children with median age 13.9 (11.3-15.7) years were recruited. The median full-scale intelligence quotient (FSIQ) was 83.0 (71.0-95.0). Below-average cognitive function (FSIQ <90) was identified in 24 children (64.8%), 24.3% of whom had cognitive impairment (FSIQ <70). Most children (94.6%) scored lower than average on at least 1 cognitive domain. Kidney replacement therapy (p = 0.03) and low family income (p = 0.02) were associated with below-average cognitive function in multivariable logistic regression analysis. Children who left school and low family income were significantly associated with cognitive function. The FSIQ of children who had left school was 12.94 points lower than the educated group (p = 0.046). In addition, every 10,000 Thai Baht (approximately 330 United States dollars) increase in family income correlated with 1.58 increase in FSIQ (p = 0.047). Cognitive dysfunction was commonly found in children with CKD. Socioeconomic factors, particularly school attendance and family income, were associated with cognitive dysfunction. Cognitive evaluation is suggested for children with CKD who have socioeconomic risk factors. "A higher resolution version of the Graphical abstract is available as Supplementary information."


Hypertension and depressed symptomatology: a cluster related to the activation of the renin-angiotensin-aldosterone system (RAAS). Findings from population based KORA F4 study.
Preliminary evidence points to aldosterone being not only prominently involved in the systemic regulation of the blood pressure but also to play a role in the pathophysiology of depression. We evaluated whether the combination of hypertension and depressed symptomatology is useful to screen for individuals suffering an activation of the renin-angiotensin-aldosterone system (RAAS). We conducted a cross-sectional analysis in participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4 Study conducted between 2006 and 2008 in Southern Germany. A total of 1805 participants of the F4 study were included in the study. The association between aldosterone and renin levels and the different combinations of hypertension and depressed symptomatology was examined in four different models of multiple linear regression adjusted for age, sex, creatinine levels, potassium levels, body mass index (BMI) and behavioural risk factors. Individuals suffering both, depressed symptomatology and hypertension exhibited highly significantly increased aldosterone levels (p<0.001) and slightly, not significantly increased renin levels (p=0.08) compared to individuals with no depressed symptomatology and no hypertension. No significant activation of the RAAS was seen in only depressed or only hypertensive individuals. The finding of highly significantly increased aldosterone levels and increased renin levels in individuals suffering both, depressed symptomatology and hypertension provides further evidence for the involvement of the RAAS in the pathogenesis of depressed symptomatology. These findings have important implications for future research concerning the pathophysiological pathways that link depression and cardiovascular disease.


Optimized numerical solutions of SIRDVW multiage model controlling SARS-CoV-2 vaccine roll out: An application to the Italian scenario.
In the context of SARS-CoV-2 pandemic, mathematical modelling has played a fundamental role for making forecasts, simulating scenarios and evaluating the impact of preventive political, social and pharmaceutical measures. Optimal control theory represents a useful mathematical tool to plan the vaccination campaign aimed at eradicating the pandemic as fast as possible. The aim of this work is to explore the optimal prioritisation order for planning vaccination campaigns able to achieve specific goals, as the reduction of the amount of infected, deceased and hospitalized in a given time frame, among age classes. For this purpose, we introduce an age stratified SIR-like epidemic compartmental model settled in an abstract framework for modelling two-doses vaccination campaigns and conceived with the description of COVID19 disease. Compared to other recent works, our model incorporates all stages of the COVID-19 disease, including death or recovery, without accounting for additional specific compartments that would increase computational complexity and that are not relevant for our purposes. Moreover, we introduce an optimal control framework where the model is the state problem while the vaccine doses administered are the control variables. An extensive campaign of numerical tests, featured in the Italian scenario and calibrated on available data from Dipartimento di Protezione Civile Italiana, proves that the presented framework can be a valuable tool to support the planning of vaccination campaigns. Indeed, in each considered scenario, our optimization framework guarantees noticeable improvements in terms of reducing deceased, infected or hospitalized individuals with respect to the baseline vaccination policy.


Effect of Iron Deficiency Anemia on Glycated Albumin Levels: A Comparative Study in Nondiabetic Subjects with Iron Deficiency Anemia.
Objective Glycated hemoglobin A1c (HbA1c), used for monitoring glycemia control, is altered in iron deficiency anemia (IDA). Glycated albumin (GA) is considered an alternate biomarker to HbA1c. However, effect of IDA on GA needs to be studied. Materials and Methods Thirty nondiabetic cases with IDA and 30 healthy controls were included. Fasting plasma glucose (FPG), creatinine, urea, albumin, total protein, ferritin, iron, unsaturated iron binding capacity, hemoglobin (Hb), HbA1c, complete hemogram, and GA were estimated. Transferrin saturation and total iron binding capacity (TIBC) were calculated. Statistical analysis was done using unpaired two-tailed t -test/Mann-Whitney U -test and Pearson's correlation/Spearman-rank correlation, as appropriate. Results Total protein, albumin, Hb, iron, ferritin, and transferrin saturation were significantly lower while FPG, GA, TIBC, and HbA1c were significantly higher in cases compared to controls. HbA1C and GA have a significant negative correlation with iron, transferrin saturation, and ferritin. Significant negative correlations of GA with albumin ( r = -0.754; p < 0.001) and Hb ( r = -0.435; p = 0.001) and that of HbA1c with albumin ( r = -0.271; p = 0.03) and Hb ( r = -0.629; p < 0.001) while significant positive correlation of Hb with albumin ( r = 0.395; p = 0.002) and HbA1c with FPG ( r = 0.415; p = 0.001) were observed. Conclusion Low albumin levels increase plasma protein glycation, including albumin. Hence, elevated GA levels indicate false elevation of GA in scenario of lowered albumin observed in IDA, similar to HbA1c. Thus, using GA in diabetes mellitus with IDA should be avoided or used with caution to prevent potentially inappropriate treatment intensification and risk of hypoglycemia.


Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma.
T1/ST2, a member of the interleukin (IL)-1 receptor superfamily, is predominantly expressed on type-2 T helper (Th2) cells but not Th1 cells, and plays a role in cell proliferation and Th2 immune response. The relation of soluble ST2, Th1-Th2 cytokine profile, and immunoglobulin (Ig) production in sepsis and trauma patients is not well known. Case-control study at a university hospital intensive care unit. Fifteen patients recruited within 24-48 h of diagnosis of sepsis, 13 trauma patients recruited within 24 h after admission to the ICU, 11 patients who underwent abdominal surgery, and 15 healthy volunteers served as control. ELISA was utilized to detect serum soluble ST2, IL-2, IFN-gamma, IL-10, and Ig production. Serum levels of soluble ST2 were significantly increased in septic patients (8420+/-2169 pg/ml) as compared with trauma (2936+/-826 pg/ml), abdominal surgery (1423+/-373 pg/ml), and healthy controls (316+/-72 pg/ml; p<0.001, respectively). These results were accompanied by an increase of IgG1 and IgG2 production, and decrease of IL-2 and IFN-gamma synthesis in septic patients. IL-10 was significantly increased in both septic and trauma patients. Our results demonstrate that soluble ST2, a marker for Th2 cytokine producing cells, is increased in sepsis and trauma patients, and they provide further evidence for a shift from Th1- to Th2-biased cells.


Extracellular Microenvironmental Change by B16F10 Melanoma-derived Proteins Induces Cancer Stem-like Cell Properties from NIH3T3 Cells.
Cancer stem-like cells (CSCs) can generate solid tumors through the properties of stem cells such as self-renewal and differentiation and they cause drug resistance, metastasis and recurrence. Therefore, establishing CSC lines is necessary to conduct various studies such as on the identification of CSC origin and specific targeted therapies. In this study, we stimulated NIH3T3 fibroblasts to exhibit the characteristics of CSCs using the whole protein lysates of B16F10 melanoma cells. As a result, we induced colony formation that displayed self-renewal and differentiation capacities through anchorage-independent culture and re-attached culture. Moreover, colonies showed drug resistance by being maintained in the G0/G1 state. Colonies expressed various CSC markers and displayed high-level drug efflux capacity. Additionally, colonies clearly demonstrated tumorigenic ability by forming a solid tumor in vivo. These results show that proteins of cancer cells could transform normal cells into CSCs by increasing expression of CSC markers. This study argues the tremendous importance of the extracellular microenvironmental effect on the generation of CSCs. It also provides a simple experimental method for deriving CSCs that could be based on the development of targeted therapy techniques.


Cx43 gap junctions in cardiac development.
Studies utilizing knockout and transgenic mouse models revealed an important role for connexin 43 (Cx43) gap junctions in cardiac development. This may involve a quantitative requirement for gap junctions in modulating the development of cardiac crest cells. In addition, studies in humans and Xenopus indicate that Cx43 gap junctions also may play a role in regulating heart laterality. Together, these findings indicate that the perturbation of Cx43 function could play a significant role in specific congenital heart malformations.


The correlation between upper body grip strength and resting-state EEG network.
Current research in the field of neuroscience primarily focuses on the analysis of electroencephalogram (EEG) activities associated with movement within the central nervous system. However, there is a dearth of studies investigating the impact of prolonged individual strength training on the resting state of the brain. Therefore, it is crucial to examine the correlation between upper body grip strength and resting-state EEG networks. In this study, coherence analysis was utilized to construct resting-state EEG networks using the available datasets. A multiple linear regression model was established to examine the correlation between the brain network properties of individuals and their maximum voluntary contraction (MVC) during gripping tasks. The model was used to predict individual MVC. The beta and gamma frequency bands showed significant correlation between RSN connectivity and MVC (p < 0.05), particularly in left hemisphere frontoparietal and fronto-occipital connectivity. RSN properties were consistently correlated with MVC in both bands, with correlation coefficients greater than 0.60 (p < 0.01). Additionally, predicted MVC positively correlated with actual MVC, with a coefficient of 0.70 and root mean square error of 5.67 (p < 0.01). The results show that the resting-state EEG network is closely related to upper body grip strength, which can indirectly reflect an individual's muscle strength through the resting brain network.


Periostin modulates extracellular matrix behavior in tendons.
Periostin, originally named osteoblast-specific factor 2 (OSF-2) has been identified primarily in collagen rich, biomechanically active tissues where its role has been implicated in mechanisms to maintain the extracellular matrix (ECM), including collagen fibrillogenesis and crosslinking. It is well documented that periostin plays a role in wound healing and scar formation after injury, in part, by promoting cell proliferation, myofibroblast differentiation, and/or collagen fibrillogenesis. Given the significance of periostin in other scar forming models, we hypothesized that periostin will influence Achilles tendon healing by modulating ECM production. Therefore, the objective of this study was to elucidate the effects of periostin during Achilles tendon healing using periostin homozygous (Postn -/-) and heterozygous (Postn +/-) mouse models. A second experiment was included to further examine the influence of periostin on collagen composition and function using intact dorsal tail tendons. Overall, Postn -/- and Postn +/- Achilles tendons exhibited impaired healing as demonstrated by delayed wound closure, increased type III collagen production, decreased cell proliferation, and reduced tensile strength. Periostin ablation also reduced tensile strength and stiffness, and altered collagen fibril distribution in the intact dorsal tail tendons. Achilles tendon outcomes support our hypothesis that periostin influences healing, while tail tendon results indicate that periostin also affects ECM morphology and behavior in mouse tendons.


Evaluation and management of the dizzy patient.
Evaluation and management of the dizzy patient remains frustrating to both the patient and physician. Numerous disorders may induce dizziness; these include not only inner ear disoders but also various central nervous system, ocular, and general systemic disturbances. Since dizziness has many variations, the subtle nuances the symptom may manifest must be explored throughly. Similarly, a consistent approach to the patient's physical and larboratory examination must be taken to understand the pathophysiology of the dizziness. This includes comprehensive auditory and vestibular evaluation, complete neurologic and ophthalmologic examination, and laboratory evaluation for latent or manifest systemic disease. The management of dizziness and vertigo is largely symptomatic. Certain exceptions exist where specific medical and surgical approaches may be beneficial, but the limitations of such treatment must be appreciated.


Generation of fruit and vegetable wastes in the farmers' market and its influencing factors: A case study from Hangzhou, China.
There remains little understanding of fruit and vegetable wastage and the influencing factors within retail. This study aimed to examine the processes contributing to vegetable and fruit wastage in traditional farmers' markets widely existing in China, Thailand, and South Korea, with the farmers' market in Hangzhou, China used as a case study. Questionnaires and follow-up surveys were conducted with the market stakeholders (market managers, retailers, and market cleaners) from April 2021 to January 2022. The results showed that the categories of discarded fruits and vegetables were related to their sales varieties, with leaf vegetables and bananas constituting the categories of vegetables and fruit with the most daily wastage. Wastage of fruits and vegetables mostly occurred in the morning. However, there was seasonal variation in fruit and vegetable wastage, with wastage in summer exceeding that in winter. The quantity of fruit and vegetable wastage was related to the size of the farmers' market. The volume of sales was also shown to be positively correlated to wastage. The analysis showed that the rank of factors influencing fruit and vegetable sales was: market service community size > appearance of fruits and vegetables > weather > market environment > fruit and vegetable price > fruit and vegetable origin. Finally, most stakeholders were motivated to reduce wastage, with their motivations including ethics, legal requirements, and economic reasons. The results of this study can act as an important reference for improving the management fruit and vegetable waste.


Hormonal contraceptive discontinuation patterns according to formulation: investigation of associations in an administrative claims database.
Hormonal contraceptive use is generally characterized by poor adherence and relatively high discontinuation. This study investigated whether specific hormonal contraceptive formulations and/or delivery systems might be correlated with discontinuation of contraception. This was a retrospective descriptive analysis within a large administrative claims database. The sample included women aged 15-40 years with a pharmacy benefit and at least one new hormonal contraception prescription during the study period and no prescription in the previous 6 months. Filled contraceptive prescriptions were grouped into several categories of delivery system, dosage, progestin type and monophasic vs. triphasic formulations. In each, a baseline number of women was established who filled a first prescription for a contraceptive formulation in the specified category. Then, the percentage of these women who filled a prescription for a contraceptive in the same category within 3 months' time was determined. Continuation or change rates were compared within each group. Oral contraceptives (OCs) were the least likely to be discontinued at 3 months; injectables were the most likely. OC formulations associated with increased risk of discontinuation (odds ratios above 1.3 representing a 5% or higher increased discontinuation) included very-low-dose (20-25 mcg ethinyl estradiol) pills containing norethindrone acetate or norgestimate, as compared to a preparation with the same progestin type but with a higher dose of estrogen. Desogestrel and norethindrone-containing triphasics were more likely to be discontinued than other triphasic progestins. OC formulations with desogestrel and norethindrone/norethindrone acetate were more likely than formulations with other progestins to be discontinued overall. This investigation in a sample of nearly 250,000 women suggests possible associations between discontinuation of hormonal contraception and factors such as estrogen dosing, progestin type and changes in dosage during the cycle. Identification of factors correlated with contraceptive discontinuation may inform management and improve adherence.


Profound effects of gastric secretion rate variations on the precipitation of erlotinib in duodenum - An in vitro investigation.
Using an artificial stomach and duodenum (ASD), we investigated the pH-dependent precipitation of erlotinib (ERL) during dissolution in the gastrointestinal (GI) tract by varying the rate of gastric fluid secretion (RGFS). Results show that decreasing RGFS from 2.5 to 0.5 mL/min leads to an increased degree of supersaturation in the duodenum fluid due to elevated pH, resulting in precipitation of ERL and a reduced area under the curve (AUC) of the concentration - time profiles from 14,000 to 3,000 (μg‧min)/mL. Such a change in AUC is expected to lower the bioavailability of ERL, a BCS II drug, in patients with a low RGFS. This example demonstrates the potential use of ASD as an effective tool for guiding the efficient development of robust tablet formulations by better understanding the impact of GI tract pH on the fate of drugs in the duodenal fluid.


Evaluation of plasma C3d and immune complex determinations in the assessment of disease activity of patients with rheumatoid arthritis, systemic lupus erythematosus, and spondylitis ancylopoetica.
Patients with rheumatoid arthritis, systemic lupus erythematosus, and spondylitis ancylopoetica were examined, along with healthy controls, for C3d plasma levels, circulating immune complexes, C3 serum levels, and CRP. Immune complexes were determined using a Clq binding assay, a 2.75% PEG precipitation technique, including the analysis of IgG and C3, and a new laser nephelometric latex test. C3d plasma levels were significantly (P less than 1%) elevated in all groups of patients as compared to controls. With regard to the demonstration of circulating immune complexes, the PEG precipitation method discriminated best between patients and the control population. It was not possible to differentiate between the different disease entities with neither C3d serum levels or immune complexes. Concerning the assessment of disease activity, none of the evaluated parameters alone appears to be of clinical relevance. The individual application of more than one immune complex assay in combination with the measurement of C3d serum levels must be recommended if disease activity is to be assessed.


Infective endocarditis associated with spondylodiscitis and frequent secondary epidural abscess.
Although many patients with IE complain of joint, muscle, and back pain, infections at these sights are rare. Indeed, in patients with back pain and endocarditis, less than 4% actually demonstrate spondylodiscitis. We recently encountered 4 patients with this complication, one each caused by Staphylococcus aureus, Streptococcus bovis, Streptococcus mitis, and Enterococcus faecalis, and wondered whether the nature of the infecting organism determined the development of spondylodiscitis and epidural abscess. In a literature review, 36 patients with endocarditis and spondylodiscitis were identified. Only 9 (25%) were caused by Streptococcus viridans and the remainder by staphylococci, enterococci, and other streptococci. Usually more than 50% of all cases of IE were caused by Streptococcus viridans, although more recent studies would indicate an incidence of about 40%. We conclude that spondylodiscitis with epidural abscess is more likely to occur in those patients with endocarditis who are infected by organisms with pyogenic potential.


Improving preventive service delivery at adult complete health check-ups: the Preventive health Evidence-based Recommendation Form (PERFORM) cluster randomized controlled trial.
To determine the effectiveness of a single checklist reminder form to improve the delivery of preventive health services at adult health check-ups in a family practice setting. A prospective cluster randomized controlled trial was conducted at four urban family practice clinics among 38 primary care physicians affiliated with the University of Toronto. Preventive Care Checklist Forms were created to be used by family physicians at adult health check-ups over a five-month period. The sex-specific forms incorporate evidence-based recommendations on preventive health services and documentation space for routine procedures such as physical examination. The forms were used in two intervention clinics and two control clinics. Rates and relative risks (RR) of the performance of 13 preventive health maneuvers at baseline and post-intervention and the percentage of up-to-date preventive health services delivered per patient were compared between the two groups. Randomly-selected charts were reviewed at baseline (n = 509) and post-intervention (n = 608). Baseline rates for provision of preventive health services ranged from 3% (fecal occult blood testing) to 93% (blood pressure measurement), similar to other settings. The percentage of up-to-date preventive health services delivered per patient at the end of the intervention was 48.9% in the control group and 71.7% in the intervention group. This is an overall 22.8% absolute increase (p = 0.0001), and 46.6% relative increase in the delivery of preventive health services per patient in the intervention group compared to controls. Eight of thirteen preventive health services showed a statistically significant change (p < 0.05) in favor of the intervention (adjusted RR (95% C.I.)): counseling on brushing/flossing teeth (9.2 (4.3-19.6)), folic acid counseling (7.5 (2.7-20.8)), fecal occult blood testing (6.7 (1.9-24.1)), smoking cessation counseling (3.9 (2.2-7.2)), tetanus immunization (3.0 (1.7-5.2)), history of alcohol intake (1.33 (1.2-1.5)), history of smoking habits (1.28 (1.2-1.4)) and blood pressure measurement (1.05 (1.00-1.10)). This simple, low cost, clinically relevant intervention improves the delivery of preventive health services by prompting physicians of evidence-based recommendations in a checklist format that incorporates existing practice patterns. Periodic updates of the Preventive Care Checklist Forms will allow a feasible and easy-to-use tool for primary care physicians to provide evidence-based preventive health services to adults at routine health check-ups. The forms can also be incorporated into an electronic health record. The Preventive Care Checklist Forms are accessible in English and French at the College of Family Physicians of Canada web site.


Blood group A antigen site distribution and immunoglobulin binding in relation to red cell age.
Heterogeneity of alpha antigen site density was demonstrated on individual human A1 and A2 type red cells by immunoelectronmicroscopy using haemocyanin-conjugated antiglobulin. Examination of red cells fractionated on a Percoll density gradient showed that the heterogeneity was not age-related. The presence of autologous immunoglobulin on senescent red cells was also confirmed by the same technique.


Transnational commercial surrogacy in India: gifts for global sisters?
In this ethnography of transnational commercial surrogacy in a small clinic in India, the narratives of two sets of women involved in this new form of reproductive travel – the transnational clients and the surrogates themselves – are evaluated. How do these women negotiate the culturally anomalous nature of transnational surrogacy within the unusual setting of India? It is demonstrated that while both sets of women downplay the economic aspect of surrogacy by drawing on predictable cultural tools like 'gift', 'sisterhood' and 'mission', they use these tools in completely unexpected ways. Previous ethnographies of surrogacy in other parts of the world have revealed that women involved in surrogacy use these narratives to downplay the contractual nature of their relationship with each other. Ironically, when used in the context of transnational surrogacy in India, these narratives further highlight and often reify the inequalities based on class, race and nationality between the clients and suppliers of reproductive tourism in India.


Predicting the risk of amputation and death in patients with diabetic foot ulcer. A long-term prospective cohort study of patients in Tanzania.
This prospective cohort study aimed to identify the characteristics of patients with diabetic foot ulcer who are at higher risk of amputation and at increased risk of death. About 103(M/F:60/43) participants, with active foot ulcer at baseline, participated in this study and followed for 22 years till death or lost to follow-up. Ten clinical measures were collected at baseline. During the follow-up of 4.2 ± 5.4 years, 22(M/F:14/8) participants had an amputation and 50(M/F:32/18) participants passed away during 5.5 ± 5.8 years follow-up period. Cox Proportional Hazard regression (HR[95%CI]) indicated neuropathy (6.415[1.119-36.778]); peripheral arterial disease (PAD) (9.741[1.932- 49.109]); current smoking (16.148[1.658-157.308]); diabetes type- 1 (3.228[1.151-9.048]) and longer delay attending appointment after ulcer (1.013[1.003-1.023]) were significantly (p < .05) associated with increased risk of amputation. In addition, death was significantly associated with the risk of amputation (3.458[1.243-9.621]). Three parameters (HR[95%CI]) including neuropathy (3.058[1.297-7.210]); PAD (5.069[2.113-12.160]); amputation history (3.689[1.306-10.423]) and retinopathy (2.389[1.227-4.653]) were all significantly associated with increased risk of death. Kaplan-Meier survival analyses indicates that the time to amputation in years for participants who eventually died was significantly shorter (11.122 ± 1.507) vs those who stayed alive (15.427 ± 1.370). Neuropathy and PAD were the only two characteristics that increased both the risk of amputation and death. Amputation showed to contribute to an increased risk of death and those participants who eventually died had a higher risk of amputation. Delay in attending appointments after ulceration is shown to increase the risk of amputation. In addition, the participants with PAD showed a significantly shorter time to both amputation and death while neuropathy was only associated with decreased time to death. Amputation history and death during follow-up decrease the time to death and amputation respectively.


Should I Stay or Should I Go: eIF3 Remains Ribosome Associated and Is Required for Elongation.
Wagner et al. (2020), Bohlen et al. (2020), and Lin et al. (2020) use Sel-TCP-seq or selective ribosome profiling to gain insights into mRNA translation initiation, highlighting distinctions between yeast and higher eukaryotes and a role for eIF3 in elongation.


Lobulated tumor contour as a predictor of preoperative tumor invasion of the lung or pericardium in thymoma patients.
Preoperative investigations to detect invasion to neighboring organs are important for deciding on the most appropriate surgical approach for thymoma. We evaluated preoperative computed tomography (CT) findings in thymoma patients to identify the CT features associated with tumor invasion. Clinicopathologic information on 193 patients who underwent surgical resection for thymoma at Chiba University Hospital between 2002 and 2016 was collected retrospectively. The surgical pathology identified invasion of thymoma in 35 patients: in the lung (n = 18), pericardium (n = 11), or both (n = 6). Contact lengths between the tumor contour and lung (CLTL) or pericardium (CLTP) were measured at the maximum section of the tumor on axial CT. Univariate and multivariate analyses were performed to analyze the relationship between pathological invasion of the lung or pericardium and the clinicopathologic features. The mean CLTL and CLTP were significantly longer in patients with invasion of the neighboring organs than in those without invasion. A lobulated tumor contour was identified in 95.6% of the patients with invasion of the neighboring organs. A multivariate analysis revealed that a lobulated tumor contour was significantly associated with both lung and pericardial invasion. A lobulated tumor contour was significantly associated with lung and/or pericardial invasion in thymoma patients.


Self-poisoning with pesticides in Jiangsu Province, China: a cross-sectional study on 24,602 subjects.
With an estimated > 800,000 suicide-related deaths and potentially several attempts for each death in the world. The purpose of this study was to determine the epidemiological characteristics of self-poisoning with pesticides within the Jiangsu province in China. Suicide rate was calculated the Routine Surveillance System by Jiangsu Provincial Center for Disease Control and Prevention, stratified by gender, age and region, combined with socioeconomic and agriculture-related factors to investigate trends in suicide over the study period. A logistic regression model was used to investigate the associations between pesticide types and pesticide-related deaths. In recent years, Jiangsu Province has witnessed a decrease in pesticide self-poisoning cases and consequent deaths. Among all suicides by deliberate ingestion of pesticides, the proportion of cases were mainly in the age 40, accounting for 3.43% of all cases with pesticide suicide. The proportion of suicide due to pesticide poisoning in females was markedly higher than that in males (p < 0.001). Suicide using organophosphate and carbamate insecticides was most common, with 10,303 reported cases accounting for 42.02% of all suicides. For national responses to be effective, the characteristics of pesticide suicides should be comprehensively investigated for the formulation of corresponding prevention strategies. At present, more pesticide suicide prevention policies for the elderly people and women should be implemented, and stronger pesticide management policies should be implemented for rural areas.


Fructose-1,6-bisphosphatase mediates cellular responses to DNA damage and aging in Saccharomyces cerevisiae.
Response to DNA damage, lack of nutrients and other stress conditions is an essential property of living systems. The coordinate response includes DNA damage repair, activation of alternate biochemical pathways, adjustment of cellular proliferation and cell cycle progression as well as drastic measures like cellular suicide which prevents proliferation of severely damaged cells. Investigating the transcriptional response of Saccharomyces cerevisiae to low doses of the alkylating agent methylmethane sulfonate (MMS) we observed induction of genes involved in glucose metabolism. RT-PCR analysis showed that the expression of the key enzyme in gluconeogenesis fructose-1,6-bisphosphatase (FBP1) was clearly up-regulated by MMS in glucose-rich medium. Interestingly, deletion of FBP1 led to reduced sensitivity to MMS, but not to other DNA-damaging agents, such as 4-NQO or phleomycin. Reintroduction of FBP1 in the knockout restored the wild-type phenotype while overexpression increased MMS sensitivity of wild-type, shortened life span and increased induction of RNR2 after treatment with MMS. Deletion of FBP1 reduced production of reactive oxygen species (ROS) in response to MMS treatment and in untreated aged cells, and increased the amount of cells able to propagate and to form colonies, but had no influence on the genotoxic effect of MMS. Our results indicate that FBP1 influences the connection between DNA damage, aging and oxidative stress through either direct signalling or an intricate adaptation in energy metabolism.


Cell surface biotinylation by azaelectrocyclization: easy-handling and versatile approach for living cell labeling.
Versatile method for living cell labeling has been established. Cell surfaces are initially biotinylated by azaelectrocyclization, and then treated with the fluorescence-labeled avidin or the anti-biotin antibody.


Pan American League of Associations for Rheumatology Guidelines for the Treatment of Takayasu Arteritis.
To develop the first evidence-based Pan American League of Associations for Rheumatology (PANLAR) guidelines for the treatment of Takayasu arteritis (TAK). A panel of vasculitis experts developed a series of clinically meaningful questions addressing the treatment of TAK patients in the PICO (population/intervention/comparator/outcome) format. A systematic literature review was performed by a team of methodologists. The evidence quality was assessed according to the GRADE (Grading of Recommendations/Assessment/Development/Evaluation) methodology. The panel of vasculitis experts voted each PICO question and made recommendations, which required ≥70% agreement among the voting members. Eleven recommendations were developed. Oral glucocorticoids are conditionally recommended for newly diagnosed and relapsing TAK patients. The addition of nontargeted synthetic immunosuppressants (e.g., methotrexate, leflunomide, azathioprine, or mycophenolate mofetil) is recommended for patients with newly diagnosed or relapsing disease that is not organ- or life-threatening. For organ- or life-threatening disease, we conditionally recommend tumor necrosis factor inhibitors (e.g., infliximab or adalimumab) or tocilizumab with consideration for short courses of cyclophosphamide as an alternative in case of restricted access to biologics. For patients relapsing despite nontargeted synthetic immunosuppressants, we conditionally recommend to switch from one nontargeted synthetic immunosuppressant to another or to add tumor necrosis factor inhibitors or tocilizumab. We conditionally recommend low-dose aspirin for patients with involvement of cranial or coronary arteries to prevent ischemic complications. We strongly recommend performing surgical vascular interventions during periods of remission whenever possible. The first PANLAR treatment guidelines for TAK provide evidence-based guidance for the treatment of TAK patients in Latin American countries.


A novel aptamer-based competition strategy for ultrasensitive electrochemical detection of leukemia cells.
A robust, nanobiotechnology-based electrochemical cytosensing platform for the detection of acute leukemia cells was developed with high sensitivity, selectivity, acceptable rapidity and excellent extensibility. It utilized the competitive binding of cell-specific aptamers to acute leukemia cells and subsequent voltammetric quantification of the metal signature. Greatly enhanced sensitivity was achieved with dual signal amplification by using Fe3O4 magnetic nanoparticles (MNPs) as carriers to load a large amount of gold nanoparticles (AuNPs) and AuNP-catalyzed silver deposition. The proposed competitive cytosensor showed high sensitivity with a detection limit down to 10 cells. This simple and low-cost electrochemical cytosensing approach offers great promise to extend its application to early detection of human leukemia and possibly to other cancer cells.


Pseudoaneurysm of mitro-aortic intervalvular fibrosa during the course of mitral valve endocarditis with aorto-left ventricle outflow tract fistula.
The mitro-aortic intervalvular fibrosa (MAIVF) connects the anterior mitral leaflet to the posterior portion of the aortic annulus. The pseudoaneurysm of MAIVF is one of the uncommon but catastrophic complications of native or prosthetic aortic valve endocarditis or chest trauma. We report a case of infective endocarditis of mitral valve complicated by development of pseudoaneurysm of MAIVF, and fistulous formation causing massive shunt flow from the ascending aorta above the non-coronary cusp to the left ventricle outflow tract.


Ecdysteroids are present in the blood of wild passerine birds.
Ecdysteroids (arthropod molting hormones) play an important role in the development and sexual maturation of arthropods, and they have been shown to have anabolic and "energizing" effect in higher vertebrates. The aim of this study was to assess ecdysteroid diversity, levels according to bird species and months, as well as to observe the molting status of hard ticks (Acari: Ixodidae) infesting the birds. Therefore, blood samples and ticks were collected from 245 birds (244 songbirds and a quail). Mass spectrometric analyses showed that 15 ecdysteroids were regularly present in the blood samples. Molting hormones biologically most active in insects (including 20-hydroxyecdysone [20E], 2deoxy-20E, ajugasterone C and dacryhainansterone) reached different levels of concentration according to bird species and season. Similarly to ecdysteroids, the seasonal presence of affected, apolytic ticks peaked in July and August. In conclusion, this study demonstrates the presence of a broad range and high concentrations of ecdysteroids in the blood stream of wild-living passerine birds. These biologically active, anabolic compounds might possibly contribute to the known high metabolic rate of songbirds.


Interaction of cholesterol, phospholipid and apoprotein in high density lipoprotein recombinants.
To examine the effect of incorporation of cholesterol into high density lipoprotein (HDL) recombinants, multilamellar liposomes of 3H cholesterol/14C dimyristoyl phosphatidylcholine were incubated with the total apoprotein (apoHDL) and principal apoproteins (apoA-1 and apoA-2) of human plasma high density lipoprotein. Soluble recombinants were separated from unreacted liposomes by centrifugation and examined by differential scanning calorimetry and negative stain electron microscopy. At 27 degrees C, liposomes containing up to approx. 0.1 mol cholesterol/mol dimyristoyl phosphatidylcholine (DMPC) were readily solubilized by apoHDL, apoA-1 or apoA-2. However, the incorporation of DMPC and apoprotein into lipoprotein complexes was markedly reduced when liposomes containing a higher proportion of cholesterol were used. For recombinants prepared from apoHDL, apoA-1, or apoA-2, the equilibrium cholesterol content of complexes was approx. 45% that of the unreacted liposomes. Electron microscopy showed that for all cholesterol concentrations, HDL recombinants were predominantly lipid bilayer discs, approx. 160 X 55 A. Differential scanning calorimetry of cholesterol containing recombinants of DMPC/cholesterol/apoHDL or DMPC/cholesterol/apoA-1 showed, with increasing cholesterol content, a linear decrease in the enthalpy of the DMPC gel to liquid crystalline transition, extrapolating to zero enthalpy at 0.15 cholesterol/DMPC. The enthalpy values were markedly reduced compared to control liposomes, where the phospholipid transition extrapolated to zero enthalpy at approx. 0.45 cholesterol/DMPC. The calorimetric and solubility studies suggest that in high density lipoprotein recombinants cholesterol is excluded from 55% of DMPC molecules bound in a non-melting state by apoprotein.


Cytotoxicity of poly-guanidine in medulloblastoma cell lines.
Medulloblastoma (MB) is the most common pediatric brain tumor. The therapy frequently causes serious side effects, and new selective therapies are needed. MB expresses hyper sialylation, a possible target for selective therapy. The cytotoxic efficacy of a poly guanidine conjugate (GuaDex) incubated with medulloblastoma cell cultures (DAOY and MB-LU-181) was investigated. The cells were incubated with 0.05-8 µM GuaDex from 15 min to 72 h. A fluorometric cytotoxicity assay (FMCA) measured the cytotoxicity. Labeled GuaDex was used to study tumor cell interaction. FITC-label Sambucus nigra confirmed high expression of sialic acid (Sia). Immunofluorescence microscopy was used to visualize the cell F-actin and microtubules. The cell interactions were studied by confocal and fluorescence microscopy. Annexin-V assay was used to detect apoptosis. Cell cycle analysis was done by DNA content determination. A wound-healing migration assay determined the effects on the migratory ability of DAOY cells after GuaDex treatment. IC50 for GuaDex was 223.4 -281.1 nM. FMCA showed potent growth inhibition on DAOY and MB-LU-181 cells at 5 uM GuaDex after 4 h of incubation. GuaDex treatment induced G2/M phase cell cycle arrest. S. nigra FITC-label lectin confirmed high expression of Sia on DAOY medulloblastoma cells. The GuaDex treatment polymerized the cytoskeleton (actin filaments and microtubules) and bound to DNA, inducing condensation. The Annexin V assay results were negative. Cell migration was inhibited at 0.5 µM GuaDex concentration after 24 h of incubation. GuaDex showed potent cytotoxicity and invasion-inhibitory effects on medulloblastoma cells at low micromolar concentrations. GuaDex efficacy was significant and warrants further studies.


Aiming for Progress in Understanding Underwater Noise Impact on Fish: Complementary Need for Indoor and Outdoor Studies.
Anthropogenic noise can be detrimental to aquatic life through physical harm and behavioral impact. Physical harm to fish only occurs very close to typically brief but high-power sources. Behavioral impact occurs at more moderate levels and is spatially and temporally much more widespread. More studies are needed to get a better understanding of the behavioral impact on fish. Indoor and outdoor studies vary in their acoustic and behavioral validity and in the amount of experimental control. Although each approach has its limitations, scientific progress and applied insights will depend on the exploitation of their complementary potential.


Longitudinal stability of progression-related microglial activity during teriflunomide treatment in patients with multiple sclerosis.
The aim was to study brain innate immune cell activation in teriflunomide-treated patients with relapsing-remitting multiple sclerosis. Imaging with 18-kDa translocator protein positron emission tomography (TSPO-PET) using the [11 C]PK11195 radioligand was employed to assess microglial activity in the white matter, thalamus and areas surrounding chronic white matter lesions in 12 patients with relapsing-remitting multiple sclerosis who had been treated with teriflunomide for at least 6 months before inclusion. Magnetic resonance imaging (MRI) was used to measure lesion load and brain volume, and quantitative susceptibility mapping (QSM) was used to detect iron rim lesions. These evaluations were repeated after 1 year of inclusion. Twelve age- and gender-matched healthy control subjects were imaged for comparison. Half of the patients had iron rim lesions. In TSPO-PET, the proportion of active voxels indicating innate immune cell activation was slightly greater amongst patients compared with healthy individuals (7.7% vs. 5.4%, p = 0.033). The mean distribution volume ratio of [11 C]PK11195 was not significantly different in the normal-appearing white matter or thalamus amongst patients versus controls. Amongst the treated patients, no significant alteration was observed in positron emission tomography distribution volume ratio, the proportion of active voxels, the number of iron-rim-positive lesions, lesion load or brain volume during follow-up. Compared to controls, treated patients exhibited modest signs of diffuse innate immune cell activity, which was unaltered during follow-up. Lesion-associated smoldering inflammation was negligible at both timepoints. To our knowledge, this is the first study applying both TSPO-PET and QSM-MRI to longitudinally evaluate smoldering inflammation.


Prognostic Value of Ezrin in Various Cancers: A Systematic Review and Updated Meta-analysis.
More and more studies have investigated the effects of Ezrin expression level on the prognostic role in various tumors. However, the results remain controversial rather than conclusive. Here, we performed a systematic review and meta-analysis to evaluate the correlation of Ezrin expression with the prognosis in various tumors. the pooled hazard ratios (HR) with the corresponding 95% confidence intervals (95% CI) were calculated to evaluate the degree of the association. The overall results of fifty-five studies with 6675 patients showed that elevated Ezrin expression was associated with a worse prognosis in patients with cancers, with the pooled HRs of 1.86 (95% CI: 1.51-2.31, P < 0.001) for over survival (OS), 2.55 (95% CI: 2.14-3.05, P < 0.001) for disease-specific survival (DFS) and 2.02 (95% CI: 1.13-3.63, P = 0.018) for disease-specific survival (DSS)/metastasis-free survival (MFS) by the random, fixed and random effect model respectively. Similar results were also observed in the stratified analyses by tumor types, ethnicity background and sample source. This meta-analysis suggests that Ezrin may be a potential prognostic marker in cancer patients. High Ezrin is associated with a poor prognosis in a variety of solid tumors.


Enhanced killing of mammalian cells by radiation combined with m-AMSA.
m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30 min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended.


Definition and epidemiology of acute heart failure syndromes.
Heart failure (HF) has emerged as a major public health issue and is among the most significant causes of morbidity and mortality for older adults in Western countries. Acute HF syndromes (AHFS) encompass many important etiologies and comorbidities. There are several different clinical definitions and classifications of AHFS that are based on their clinical picture and pathophysiology. These definitions and classifications should, at best, serve to individually tailor diagnostics and therapy. Another important application of these definitions and classifications is to help guide future clinical trials in AHFS. The epidemiology of AHFS has been studied in large and small registries and surveys in both North America and Europe. The properties of the population of patients with acute HF are discussed in light of these data.


[Disproportionately increased incidence of proximal femoral fractures in a level one trauma center : Epidemiological analysis from 2016 to 2022].
Proximal femoral fractures represent the most frequent fracture entity in Germany accounting for more than 20% of all fractures. According to a decision of the Federal Joint Committee from 2019, proximal femoral fractures also have to be surgically treated within 24 h. In order to quantify a subjectively perceived increase in workload in trauma surgery at a supraregional trauma center, a retrospective analysis of the number of surgically treated proximal femoral fractures was performed. Proximal femoral fractures were chosen due to their high incidence and homogeneous treatment. Using ICD-10 codes, all surgically treated proximal femoral fractures from 2016 to 2022, including the patient's zip code, were retrieved from the database of the trauma center. The number of surgically treated proximal femoral fractures doubled from 2016 to 2022. The highest increase (60%) was recorded from 2020 to 2022. Heat maps show an increase in the catchment area radius as well. When compared (inter)nationally, a disproportionate increase in the amount of surgically treated proximal femoral fractures was recorded at the trauma center studied. The increase of the catchment area radius and the number of patients treated in the urban area show that less and less hospitals participate in emergency treatment. Possible explanations are a lack of resources aggravated by the recent COVID-19 pandemic and a lack of qualified personnel, interface problems between the federal states or the strict requirements of the Federal Joint Committee in the treatment of proximal femoral fractures. It must be assumed that there is a clearly increased workload for all professions involved in the trauma center investigated, although the infrastructure has remained unchanged.