Gender, sex-steroid, and secretagogue-selective recovery from growth hormone-induced feedback in older women and men.
GH negatively regulates its own secretion. How gender, sex steroids, and secretagogues modulate GH autofeedback is not known. Supplementation with sex steroids and/or a peptidyl secretagogue will enhance the escape of GH from autoinhibition, thus framing a mechanism for amplifying pulsatile GH secretion. Ten healthy postmenopausal women and 10 comparably aged men participated at the Clinical-Translational Science Unit. Randomly ordered, double-blind, prospective crossover treatment with placebo vs. testosterone (men) or placebo vs. estradiol (women). Autofeedback was imposed by an iv pulse of GH. Recovery of feedback inhibition was quantified during constant infusion of saline, GHRH, or GH-releasing peptide-2 (three peptide categories). During negative feedback, total (integrated) GH recovery depended upon gender (P = 0.017), sex hormone (P < 0.001), and peptide category (P < 0.001). Mechanistic analysis revealed that feedback-suppressed nadir GH concentrations were determined by sex-steroid treatment (P = 0.018) but not by gender (P = 0.444). Peak GH escape was controlled by both treatment (P = 0.004) and gender (P = 0.003). Nadir GH and peak GH during feedback were enhanced by GHRH or GHRP-2 (P < 0.001 for both). Gender × peptide (P = 0.012 for nadir GH), treatment × peptide (P < 0.001 total and peak GH), and gender × treatment (P = 0.017 nadir GH) regulated GH recovery interactively. Gender, sex-steroid supplementation, and secretagogue type confer distinct feedback-rescuing effects, introducing a new level of complexity in the control of pulsatile GH regulation.


Effectiveness of endoscopic transsphenoidal surgery for gonadotroph adenoma mimicking dementia: A case report.
There are few reports of pituitary adenomas (PA) mimicking dementia. Delay in disease diagnosis and treatment may result in poor clinical outcome. We experienced a rare case where endoscopic transsphenoidal surgery (eTSS) effectively treated a gonadotroph adenoma mimicking dementia and report on literature considerations. We report the case of a 72-year-old man with chief complaints of cognitive decline, bradykinesia, anorexia, dressing apraxia, and vigor decline over several months. He was admitted to our hospital for scrutiny in a disoriented state. Blood tests showed hyponatremia and thyroid hormone depression. Magnetic resonance imaging showed a pituitary tumor, and preoperative endocrine stress tests showed reduced reactivities of growth hormone, adrenocorticotropic hormone/cortisol, and luteinizing hormone/follicle-stimulating hormone. Symptomatic pituitary adenoma was suspected, and eTSS was performed. The permanent pathological diagnosis was of gonadotroph adenoma. Postoperatively, the hyponatremia, cognitive decline, movement retardation, loss of appetite, dressing apraxia, and limb edema markedly improved. The patient was discharged under hydrocortisone 15 mg/day administration without complications. The endocrine stress test performed 2 months postoperatively showed secondary hypoadrenocorticism, while the other endocrine functions had normalized. No recurrence had occurred by 30 months postoperatively; the medication of hydrocortisone was gradually discontinued and the patient at the time was still being followed as an outpatient with modified Rankin Scale score 0. Secondary hypothyroidism and secondary hypoadrenocorticism due to the pituitary tumor primarily caused the condition. It is important to consider PA in the differential diagnosis of dementia, and early diagnosis and treatment can contribute to a patient's good clinical outcome.


Regulation of pelZ, a gene of the pelB-pelC cluster encoding a new pectate lyase of Erwinia chrysanthemi 3937.
The phytopathogenic enterobacterium Erwinia chrysanthemi 3937 produces five major and several secondary endo-pectate lyases encoded by the pel genes. Most of these genes are arranged in clusters on the bacterial chromosome. The genomic region surrounding the pelB-pelC cluster was supposed to be involved in the regulation of PelB and PelC synthesis. We demonstrated that the variation of pelB expression resulted from the titration of a regulatory protein by the gene adjacent to pelC. This gene was renamed pelZ since it encodes a protein of 420 amino acids with an endo-pectate lyase activity. Regulation of pelZ expression was investigated by using transcriptional fusions and a study of mRNA synthesis. Its transcription depends on different environmental conditions. It is induced in planta and in the presence of pectic catabolite products. This induction seems to be partially mediated by the KdgR protein but does not result from a direct interaction of KdgR with the pelZ 5' region. The transcription of pelZ leads to the synthesis of a monocistronic mRNA. However, the synthesis of a polycistronic mRNA from the pelC promoter, regulated by KdgR, is responsible for increased production of PelZ under inducing conditions. pelZ transcription is also controlled by pecT, which regulates some other pel genes, but it is independent of the pecS regulatory locus. The pelZ gene appears to be widespread in different strains of E. chrysanthemi. Moreover, a gene homologous to pelZ exists in Erwinia carotovora subsp. atroseptica adjacent to the cluster containing the pectate lyase-encoding genes pel1, pel2, and pel3. This conservation could reflect a significant role of PelZ in the pectinolytic system of Erwiniae. We showed pelZ is not a predominant virulence factor of E. chrysanthemi but is involved in host specificity.


The business case for building better hospitals through evidence-based design.
After establishing the connection between building well-designed evidence-based facilities and improved safety and quality for patients, families, and staff, this article presents the compelling business case for doing so. It demonstrates why ongoing operating savings and initial capital costs must be analyzed and describes specific steps to ensure that design innovations are implemented effectively. Hospital leaders and boards are now beginning to face a new reality: They can no longer tolerate preventable hospital-acquired conditions such as infections, falls, and injuries to staff or unnecessary intra-hospital patient transfers that can increase errors. Nor can they subject patients and families to noisy, confusing environments that increase anxiety and stress. They must effectively deploy all reasonable quality improvement techniques available. To be optimally effective, a variety of tactics must be combined and implemented in an integrated way. Hospital leadership must understand the clear connection between building well-designed healing environments and improved healthcare safety and quality for patients, families, and staff, as well as the compelling business case for doing so. Emerging pay-for-performance (P4P) methodologies that reward hospitals for quality and refuse to pay hospitals for the harm they cause (e.g., infections and falls) further strengthen this business case. When planning to build a new hospital or to renovate an existing facility, healthcare leaders should address a key question: Will the proposed project incorporate all relevant and proven evidence-based design innovations to optimize patient safety, quality, and satisfaction as well as workforce safety, satisfaction, productivity, and energy efficiency? When conducting a business case analysis for a new project, hospital leaders should consider ongoing operating savings and the market share impact of evidence-based design interventions as well as initial capital costs. They should consider taking the 10 steps recommended to ensure an optimal, cost-effective hospital environment. A return-on-investment (ROI) framework is put forward for the use of individual organizations.


Comparative applications of azadirachtin- and Brevibacillus laterosporus-based formulations for house fly management experiments in dairy farms.
The potential of two bioinsecticidal formulations containing Brevibacillus laterosporus spores and azadirachtin, respectively, was assayed in laboratory and in comparative field treatments for the management of immature house flies on dairy farms. As already known for B. laterosporus, preliminary laboratory experiments with azadirachtin evidenced a concentration-dependent effect. Azadirachtin median lethal concentration (LC50) value determined for second instar larvae was 24.5 microg/g diet. Applications in dairy farms were performed at dosages and concentrations predetermined in laboratory experiments, to employ the two formulations at an equal insecticidal potential. Repeated applications on the cow pen caused a significant fly development depression in areas treated with azadirachtin (63%) and B. laterosporus (46%), compared with the control. Formulations were applied at a dosage of 3 liters/m2, and concentrations of 2 x 10(8) B. laterosporus spores/ml and 25 microg azadirachtin/ml, respectively.


Competition between Kondo screening and indirect magnetic exchange in a quantum box.
Nanoscale systems of metal atoms antiferromagnetically exchange coupled to several magnetic impurities are shown to exhibit an unconventional reentrant competition between Kondo screening and indirect magnetic exchange interaction. Depending on the atomic positions of the magnetic moments, the total ground-state spin deviates from predictions of standard Ruderman-Kittel-Kasuya-Yosida perturbation theory. The effect shows up on an energy scale larger than the level width induced by the coupling to the environment and is experimentally accessible by studying magnetic field dependencies.


Management of diffuse tissue argyria subsequent to endodontic therapy: report of a case.
A case of severe mucogingival argyria secondary to leakage around and corrosion of silver cone root canal obturations and apical amalgam restorations is presented. Following removal of the silver points and re-treatment of the root canals, periradicular surgery was performed to remove the amalgam root-end restorations and reduce the amount of dispersed metallic particles in the subcutaneous tissues. Subsequent free gingival grafting created an esthetically pleasing and biologically acceptable result.


Toggling the Local Electric Field with an Embedded Adatom Switch.
By means of scanning probe microscopy we demonstrate that Au(+) on NaCl films adsorbs in an embedded, slightly off-centered Cl-Cl bridge position and can be switched between two equivalent mirror-symmetric configurations using the attractive force exerted by a scanning probe tip. Density functional theory calculations demonstrate that the displacement of the Au atom from the centered position of the bridge configuration is accompanied by a large lifting of the closest Cl atom leading to significant changes in the local electrostatic field. Our findings suggest that Au(+) can be used to toggle the local electrostatic field.


A Fabry-Pérot interferometer with wire-grid polarizers as beamsplitters at terahertz frequencies.
The design of a compact Fabry-Pérot interferometer (FPi) and results of the experimental studies carried out using the device are presented. Our FPi uses freestanding wire-grid polarizers (WGPs) as beamsplitters and is suitable for use at terahertz (THz) frequencies. The FPi was studied at the LUCX facility, KEK, Japan, and an 8 MeV linear electron accelerator was used to generate coherent Smith-Purcell radiation. The FPi was designed to be easy to align and reposition for experiments at linear accelerator facilities. All of the components used were required to have a flat or well understood frequency response in the THz range. The performance of the FPi with WGPs was compared to that of a Michelson interferometer and the FPi is seen to perform well. The effectiveness of the beamsplitters used in the FPi is also investigated. Measurements made with the FPi using WGPs, the preferred beamsplitters, are compared to measurements made with the FPi using silicon wafers as alternative beamsplitters. The FPi performs well with both types of beamsplitter in the frequency range used (0.3-0.5 THz). The successful measurements taken with the FPi demonstrate a compact and adaptable interferometer that is capable of analyzing THz radiation over a broad frequency range. The scheme is particularly well suited for polarization studies of THz radiation produced in an accelerator environment.


Study on retinal ganglion cell apoptosis after explosive injury of eyeballs in rabbits.
To explore the pathological changes of retinal ganglion cell apoptosis and its relation to the value of glutamate concentration in vitreous body after explosive injury of eyeballs in the rabbits. Similar explosive injury models of eyeballs in 10 adult grey rabbits were made. The rabbits were killed on scheduled time. The retinal tissues of studied eyes and control eyes were obtained for the pathological examination with TUNEL method respectively. The value of glutamate in vitreum of injured eyes was measured and was compared with that of contralateral eyes. Statistical comparison analysis on the experiment data was performed. The value of glutamate in vitreum of injured eyes was significantly higher than that of contralateral eyes in all rabbits in the study. A lot of TUNEL positive cells were observed in the injured eyes. It suggested that apoptosis of the retinal ganglion cells took place. We speculate that apoptosis of the retinal ganglion cells is perhaps among the causes resulting in damage of visual function after explosive injury of eyeballs and that the increasing of the value of glutamate in vitreum possibly associated with apoptosis of the retinal ganglion cells.


County-Level Segregation and Racial Disparities in COVID-19 Outcomes.
Segregation has been linked to unequal life chances. Individuals from marginalized communities experience more crime, higher levels of poverty, poorer health, and less civic engagement. In addition, segregated metropolitan regions have been found to display inequality in access to basic services. This article builds on these findings by linking segregation to infection and deaths from COVID-19. Using census data matched to COVID infection and death statistics at the county level, this article offers a theoretical basis for the researchers' choice of segregation measures and predictions for different racial groups. It analyzes the relationship between two dimensions of segregation-racial isolation and racial unevenness-and COVID outcomes for different racial and ethnic groups. In counties where Black and Latino residents lived in more racially isolated neighborhoods, they were much more likely to contract COVID-19. This pattern was exacerbated in counties with a high proportion of frontline workers. In addition, racial segregation increased COVID-19 death rates for Black, Latino, and white residents. These findings suggest that devastating outcomes of the coronavirus pandemic were linked to a long history of racial marginalization and entrenched discrimination produced by structural inequalities embedded in our geographies. This knowledge should be used to inform public health planning.


Biomechanical optimization of subject-specific implant positioning for femoral head resurfacing to reduce fracture risk.
Peri-prosthetic femoral neck fracture after femoral head resurfacing can be either patient-related or surgical technique-related. The study aimed to develop a patient-specific finite element modelling technique that can reliably predict an optimal implant position and give minimal strain in the peri-prosthetic bone tissue, thereby reducing the risk of peri-prosthetic femoral neck fracture. The subject-specific finite element modelling was integrated with optimization techniques including design of experiments to best possibly position the implant for achieving minimal strain for femoral head resurfacing. Sample space was defined by varying the floating point to find the extremes at which the cylindrical reaming operation actually cuts into the femoral neck causing a notch during hip resurfacing surgery. The study showed that the location of the maximum strain, for all non-notching positions, was on the superior femoral neck, in the peri-prosthetic bone tissue. It demonstrated that varus positioning resulted in a higher strain, while valgus positioning reduced the strain, and further that neutral version had a lower strain.


Child molesters vs. rapists as reflected in their self-figure drawings: a pilot study.
This study explored whether child molesters can be differentiated from rapists in their self-figure drawings. To achieve this aim, the Machover Draw-A-Person test (Machover, 1949) was used. A sample of 41 male adult perpetrators of sexual assault, 19 rapists and 22 child molesters (all incarcerated in jail) participated in the study. Participants were given paper and pencil and were asked to draw themselves. Results indicated that self-figure drawings of rapists had more indicators of a violent aggressive behavior trait than drawings of child molesters, whereas exaggeration and emphasis of penis were more obvious in the self-figure drawings of child molesters. However, indicators of anxiety were not found to significantly differ between the groups.


Thermal isotherms in PMMA and cell necrosis during total hip arthroplasty.
Polymethylmethacrylate (PMMA), also known as bone cement, is a commonly used adhesive material to fix implants in Total Hip Arthroplasty (THA). During implantation, bone cement undergoes a polymerization reaction which is an exothermic reaction and results in the release of heat to the surrounding bone tissue, which ultimately leads to thermal necrosis. Necrosis in the bony tissue results in early loosening of the implant, which causes pain and reduces the life of the implant. The main objective of the present study was to understand the thermal isotherms in PMMA and to determine the optimal cement mantle thickness to prevent cell necrosis during THA. In this study, the environment in the bony tissue during implantation was simulated by constructing 3D solid models to observe the temperature distribution in the bony tissue at different cement mantle thicknesses (1 mm, 3 mm and 5 mm), by applying the temperature conditions that exist during the surgery. Stems made with Co-Cr-Mo, 316L stainless steel and Ti6Al4V were used, which acted as heat sinks, and a thermal damage equation was used to measure the bone damage. FEA was conducted based on temperature conditions and thermal isotherms at different cement mantle thicknesses were obtained. Thermal isotherms derived with respect to distance in the bony tissue from the center of the cement mantle, and cell necrosis was determined at different mantle thicknesses. Based on the deduced results, cement mantle thickness of 1-5 mm does not cause thermal damage in the bony tissue. Considering the long term stability of the implant, cement mantle thickness range from 3 mm-5 mm was found to be optimal in THA to prevent cell necrosis.


Effect of a Digitally-Enabled, Preventive Health Program on Blood Pressure in an Adult, Dutch General Population Cohort: An Observational Pilot Study.
Worldwide, it is estimated that at least one in four adults suffers from hypertension, and this number is expected to increase as populations grow and age. Blood pressure (BP) possesses substantial heritability, but is also heavily modulated by lifestyle factors. As such, digital, lifestyle-based interventions are a promising alternative to standard care for hypertension prevention and management. In this study, we assessed the prevalence of elevated and high BP in a Dutch general population cohort undergoing a health screening, and observed the effects of a subsequent self-initiated, digitally-enabled lifestyle program on BP regulation. Baseline data were available for 348 participants, of which 56 had partaken in a BP-focused lifestyle program and got remeasured 10 months after the intervention. Participants with elevated SBP and DBP at baseline showed a mean decrease of 7.2 mmHg and 5.4 mmHg, respectively. Additionally, 70% and 72.5% of participants showed an improvement in systolic and diastolic BP at remeasurement. These improvements in BP are superior to those seen in other recent studies. The long-term sustainability and the efficacy of this and similar digital lifestyle interventions will need to be established in additional, larger studies.


Water oxidation by amorphous cobalt-based oxides: volume activity and proton transfer to electrolyte bases.
Water oxidation in the neutral pH regime catalyzed by amorphous transition-metal oxides is of high interest in energy science. Crucial determinants of electrocatalytic activity were investigated for a cobalt-based oxide film electrodeposited at various thicknesses on inert electrodes. For water oxidation at low current densities, the turnover frequency (TOF) per cobalt ion of the bulk material stayed fully constant for variation of the thickness of the oxide film by a factor of 100 (from about 15 nm to 1.5 μm). Thickness variation changed neither the nanostructure of the outer film surface nor the atomic structure of the oxide catalyst significantly. These findings imply catalytic activity of the bulk hydrated oxide material. Nonclassical dependence on pH was observed. For buffered electrolytes with pKa values of the buffer base ranging from 4.7 (acetate) to 10.3 (hydrogen carbonate), the catalytic activity reflected the protonation state of the buffer base in the electrolyte solution directly and not the intrinsic catalytic properties of the oxide itself. It is proposed that catalysis of water oxidation occurs within the bulk hydrated oxide film at the margins of cobalt oxide fragments of molecular dimensions. At high current densities, the availability of a proton-accepting base at the catalyst-electrolyte interface controls the rate of water oxidation. The reported findings may be of general relevance for water oxidation catalyzed at moderate pH by amorphous transition-metal oxides.


[Outfit for impedance studies of the auditory function].
An apparatus for measuring the middle-ear impedance enabling it to record the threshold of the acoustic reflex and to measure its dynamic characteristics with contralateral and ipsilateral stimulation, as well as to carry out tympanometry of the middle ear and to judge on the ventilation function of the auditory tube is described. The set-up includes: a device for pressure feeding and recording in the external ear, an arrangement for imparting a sonic stimulus and the one for input and recording the air pressure.


Predictors of middle school students' interest in participating in an incentive-based tobacco prevention and cessation program in connecticut.
Behavioral incentives have been used to encourage smoking cessation in older adolescents, but the acceptability of incentives to promote a smoke-free lifestyle in younger adolescents is unknown. To inform the development of novel, effective, school-based interventions for youth, we assessed middle school students' interest in participating in an incentive-based tobacco abstinence program. We surveyed 988 students (grades 6-8) attending three Connecticut middle schools to determine whether interest in program participation varied as a function of (1) intrapersonal factors (i.e., demographic characteristics (sex, age, race), smoking history, and trait impulsivity) and/or (2) aspects of program design (i.e., prize type, value, and reward frequency). Primary analyses were conducted using multiple regression. A majority of students (61.8%) reported interest in program participation. Interest did not vary by gender, smoking risk status, or offering cash prizes. However, younger students, non-Caucasian students, behaviorally impulsive students, and students with higher levels of self-regulation were more likely to report interest. Inexpensive awards (e.g., video games) offered monthly motivated program interest. In sum, middle school students reported high levels of interest in an incentive-based program to encourage a tobacco-free lifestyle. These formative data can inform the design of effective, incentive-based smoking cessation and prevention programs in middle schools.


Effects of high hydrostatic pressure on antimicrobial protein stability and the rheological and shelf-life properties of donkey milk.
The effects of high hydrostatic pressure (HHP) and heat treatments on antimicrobial protein stability and on the physico-chemical, microbiological, rheological and shelf-life properties of donkey milk were investigated. Although heat treatment at 75°C for 2 min resulted in 1.50 log CFU ml-1 microbial inactivation, losses in activities of lysozyme (58%) and lactoferrin (82%) were observed due to whey protein denaturation. By contrast, HHP application at 400 MPa caused lower enzyme activity losses (22 and 37% respectively) whilst maintaining a significant reduction of microbial load (1.80 log CFU ml-1). Color analyses showed that the lightness values of all samples decreased during storage. Higher flow consistency (viscosity) and lower flow behavior indexes were observed in heat-treated samples compared to untreated and HHP-treated ones, which can be explained by advanced protein denaturation during heat-treatment. The results suggest that HHP is a more suitable process than heat treatment for preservation of donkey milk within the conditions studied.


Molecular basis of Escherichia coli colonization of the upper urinary tract in BALB/c mice. Gal-Gal pili immunization prevents Escherichia coli pyelonephritis in the BALB/c mouse model of human pyelonephritis.
Most human pyelonephritis Escherichia coli isolates express both mannose (MS)- and globoside (Gal-Gal)-binding pili. An ascending E. coli urinary tract infection model was established in the 16-wk-old female BALB/c mouse to compare the pathogenic significance of MS and Gal-Gal pili and their efficacy as vaccines for the prevention of pyelonephritis. The distribution and density of pilus receptor compounds in urogenital tissues and as soluble compounds in urine were determined with antibodies to the synthetic receptor analogues, alpha D-Gal(1----4) beta D-Gal and alpha D-Man(1----2) alpha D-Man. Both carbohydrates were detected in vagina, bladder, ureter, and renal pelvis epithelium and in collecting duct and tubular cells. A pilus receptor compound also was detected in urine. It competitively inhibited the binding capacity of MS pili and was found to be physically, chemically, and immunologically related to Tamm-Horsfall uromucoid. Infectivity and invasiveness were quantitatively and histologically characterized for four E. coli strains: J96, a human pyelonephritis strain that expresses both MS and Gal-Gal pili; two recombinant strains prepared from J96 chromosomal DNA encoding MS pili or Gal-Gal pili; and the nonpiliated K12 recipient. Intravesicular administration of J96 (10(6) colony-forming units [CFU]) resulted in renal colonization and invasion in each of nine mice. The Gal-Gal clone (10(6) CFU) colonized the kidneys in each of 10 mice but did not invade. In contrast, the MS clone (10(6) CFU) did not colonize renal epithelium or invade. This effect was superceded when larger doses (greater than or equal to 10(10) CFU) of the MS clone were administered in volumes that cause acute vesicoureteric reflux. The efficacy was determined of vaccines composed of pure MS or Gal-Gal pili or the lipopolysaccharide containing O somatic antigen of the challenge strain, J96. The Gal-Gal pilus vaccine blocked renal colonization in 19 of 22 mice and renal invasion in 10 of 11 mice. Gal-Gal pili may be useful immunogens for the prevention of pyelonephritis in anatomically normal urinary tracts.


Oil Recovery from Micropatterned Triangular Troughs during a Surfactant Flood.
We study the recovery of oil trapped inside micropatterned triangular troughs after injecting a surfactant solution. In our experiments, we track the trapped oil volume with duration of surfactant flood for different capillary numbers. We observe that the capillary number affects the amount of oil recovered as the well as the rate of oil recovery. We employ multiphase flow simulations to analyze our system and show a qualitative agreement between the simulations and experimental results. We also discover that beyond a capillary number, the volume of oil recovered plateaus, and no additional oil is released with an increase in capillary number. We develop a theoretical model to predict the dependence of maximum oil recovery on geometrical features and find that the theoretical predictions compare favorably with the trends obtained from our simulations. Though approximate, theoretical relation provides insights into the efficiency of oil recovery and can be utilized to understand the effect of sharp bends and dead ends in enhanced oil recovery and soil remediation.


Familial myelodysplastic syndromes: a review of the literature.
Familial cases of myelodysplastic syndromes are rare, but are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general. The best-characterized familial myelodysplastic syndrome is that of familial platelet disorder with propensity to myeloid malignancy, caused by heterozygous germline RUNX1 mutations. Recently, there has been an increase in the number of reported cases, allowing for better understanding of the incidence, clinical features, and pathogenesis of this disorder. These recent cases have highlighted the clinical variability of the disorder and confirmed that many patients lack a bleeding and/or thrombocytopenia history. Additionally, several cases of T-acute lymphoblastic leukemia have now been reported, confirming a risk of lymphoid leukemia in patients with inherited RUNX1 mutations. Furthermore, an increased awareness of clinicians has helped detect a number of additional families affected by inherited myelodysplastic syndromes, resulting in the identification of novel causative mechanisms of disease, such as RUNX1 deficiency resulting from constitutional microdeletions of 21q22 and myelodysplasia-associated with telomerase deficiency. Awareness of predisposition to myelodysplastic syndromes and acute myeloid leukemia in families may be of critical importance in the management of younger patients with myelodysplasia in whom allogeneic hematopoietic stem cell transplantation is considered. Such families should be investigated for inherited deficiencies of RUNX1 and/or telomerase to prevent the use of an affected sibling as a donor for transplantation. Here we provide an update on familial platelet disorder in addition to a review of other known familial myelodysplastic syndromes.


Endovascular Treatment versus Best Medical Treatment in Patients with Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials.
Endovascular treatment has emerged as a minimally invasive technique for patients with acute ischemic stroke to achieve recanalization. Our aim was to determine the effects of endovascular treatment on clinical and safety outcomes compared with best medical treatment. Fifteen randomized trials that compared endovascular treatment with best medical treatment in patients with acute ischemic stroke met the inclusion criteria. We calculated pooled odds ratios and 95% CIs by using random-effects models. The primary end point was a favorable outcome defined by a modified Rankin Scale score of 0 (no symptoms), 1 (no significant disability), or 2 (slight disability) at 90 days postrandomization. Of the 2980 subjects randomized, the proportion of subjects who achieved a favorable outcome was significantly greater among those randomized to endovascular treatment compared with best medical treatment (2949 subjects analyzed; odds ratio, 1.82; 95% CI, 1.38-2.40; P < .001). Excellent outcome (modified Rankin Scale score of 0 or 1) was also significantly greater among those randomized to endovascular treatment (2791 subjects analyzed; odds ratio, 1.77; 95% CI, 1.29-2.43, P < .001). Risk of symptomatic intracranial hemorrhage was similar between endovascular treatment and best medical treatment (2906 subjects analyzed; odds ratio, 1.19; 95% CI, 0.84-1.68; P = .34). Compared with best medical treatment, the odds of achieving a favorable outcome or excellent outcome at 3 months postrandomization are approximately 80% higher with endovascular treatment among patients with acute ischemic stroke.


[Intravenous antimicrobial use among different hospital in Chile during 2005].
Intravenous antimicrobial consumption has not been evaluated previously in Chile. In order to know this consumption (in DDD per 100 bed days), associated factors and antimicrobial control systems across the country, a questionnaire was sent to evaluate these features during 2005. A total of 29 public hospitals and private clinics answered this poll, 20 belonging to the public health system (69%). Only 48.1% declared to have an independent antimicrobial committee and 17.2% allowed unrestricted antimicrobial use. Glycopeptides and carbapenems were the most regulated compounds (75.9 and 82.8%, respectively). Antimicrobial controls systems were more frequently declared among public hospitals and only non-public hospitals permitted free use of antimicrobials. Global consumption reached 59.98 DDD per 100 bed-days, with beta-lactams representing 74.3% of this consume (44.57 DDD per 100), and cephalosporins 43% (25.78 DDD per 100). Chloramphenicol, penicillin G and cloxacillin use was significantly higher among public hospitals. The opposite was observed for imipenem-cilastatin, linezolid, cefuroxime and caspofungin with higher consumes observed among non-public hospitals. In a multivariate analysis, increased cefazolin use was independently associated with sites allowing unrestricted use, and ciprofloxacin consumption with non-public hospitals. Institutions with decreased susceptibility to imipenem-cilastatin among non-fermentative gram negative bacilli showed a higher use of this compound and linezolid consumption paralleled vancomycin-resistant enterococci prevalence. It is necessary to reinforce governmental regulations about antimicrobial use issued during 1999.


Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli.
Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results indicate that sorafenib in vitro counteracts autocrine growth of different tumor cells (Hep3B, HepG2, PLC-PRF-5, SK-Hep1). Arrest in S/G2/M cell cycle phases were observed coincident with cyclin D1 down-regulation. However, sorafenib's main anti-tumor activity seems to occur through cell death induction which correlated with caspase activation, increase in the percentage of hypodiploid cells, activation of BAX and BAK and cytochrome c release from mitochondria to cytosol. In addition, we observed a rise in mRNA and protein levels of the pro-apoptotic "BH3-domain only" PUMA and BIM, as well as decreased protein levels of the anti-apoptotic MCL1 and survivin. PUMA targeting knock-down, by using specific siRNAs, inhibited sorafenib-induced apoptotic features. Moreover, we obtained evidence suggesting that sorafenib also sensitizes HCC cells to the apoptotic activity of transforming growth factor-β (TGF-β) through the intrinsic pathway and to tumor necrosis factor-α (TNF) through the extrinsic pathway. Interestingly, sensitization to sorafenib-induced apoptosis is characteristic of liver tumor cells, since untransformed hepatocytes did not respond to sorafenib inducing apoptosis, either alone or in combination with TGF-β or TNF. Indeed, sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro-apoptotic physiological cytokines.


Glucagon-like peptide-1 does not mediate amylase release from AR42J cells.
In this study, AR42J pancreatic acinar cells were used to investigate if glucagon-like peptide-1 (GLP-1) or glucagon might influence amylase release and acinar cell function. We first confirmed the presence of GLP-1 receptors on AR42J cells by reverse trasncriptase-polymerase chain reaction (RT-PCR), Western blotting, and partial sequencing analysis. While cholecystokinin (CCK) increased amylase release from AR42J cells, GLP-1, alone or in the presence of CCK, had no effect on amylase release but both CCK and GLP-1 increased intracellular calcium. Similar to GLP-1, glucagon increased both cyclic adenosine monophosphate (cAMP) and intracellular calcium in AR42J cells but it actually decreased CCK-mediated amylase release (n = 20, P < 0.01). CCK stimulation resulted in an increase in tyrosine phosphorylation of several cellular proteins, unlike GLP-1 treatment, where no such increased phosphorylation was seen. Instead, GLP-1 decreased such protein phosphorylations. Genestein blocked CCK-induced phosphorylation events and amylase secretion while vanadate increased amylase secretion. These results provide evidence that tyrosine phosphorylation is necessary for amylase release and that signaling through GLP-1 receptors does not mediate amylase release in AR42J cells. J. Cell. Physiol. 181:470-478, 1999. Published 1999 Wiley-Liss, Inc.


Renal transplantation in children with congenital nephrotic syndrome: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).
The database of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) was examined to identify factors that contribute to the poor transplant outcome rate seen in patients with Congenital Nephrotic Syndrome (CNS) (1). Between January 1, 1987 and January, 1997, 132 transplant recipients with the primary diagnosis of CNS were registered. Analysis of the index renal transplants for 78 living donor transplants (LDTx) and 54 cadaver transplants (CADTx) revealed a graft failure rate of 20.5% and 50.0%, respectively. A proportional hazards regression analysis of the CNS patients indicated that cadaver donor source (relative risk increase of 3.9, p<0.001) and recipient age less than 2 years of age (relative risk increase of 2.6, p=0.002) were simultaneous significant predictors of poor graft survival. Patients with CNS demonstrated decreased graft survival compared to the remainder of the registry adjusted for age and donor source (p=0.04). Graft failures were attributed to vascular thrombosis (26%), patient death with functioning graft (23%), chronic rejection (21%) and acute rejection (19%). Graft failure attributed to thrombosis occurred more frequently in CNS patients than in patients with other primary diseases (8.3% vs. 2.9%, p=0.002). Graft failure due to patient death with a functioning graft also occurred more frequently in CNS patients than in patients with other primary diseases (7.5% vs. 2.6%, p<0.003). Infections were the causes of death in 50% (5 of 10) of CNS patients with a functioning graft. Infection as a cause of death with functioning grafts was significantly greater in CNS patients (3.8%) than the rest of the registry (0.8%, p<0.006). We conclude that there is a high rate of renal graft failure in pediatric patients with CNS. Vascular thrombosis and death with a functioning graft were more frequent in patients with CNS compared to patients with other primary diseases. Care should be taken to eliminate risk factors for hypercoagulability and infections prior to transplantation in children with CNS.


Reconstruction of severe contracture of the first web space using the reverse posterior interosseous artery flap.
To evaluate the outcome and highlight the operative tips of using the reverse posterior interosseous artery (PIA) flap in the treatment of severe contractures of the first web space. From 1985 to 2008, the reverse PIA flaps, which included fasciocutaneous flaps in 25 patients and composite flaps in 2 patients were used to cover skin defects over the first web space after release of severe contractures of the first web space. The severe contracture of the first web space was defined as the distance of less than 2 cm between the interphalangeal joint of the thumb and the metacarpophalangeal joint of the index. The flap dimensions varied between 6 cm and 22 cm (average, 13 cm) in length and 3 cm to 9 cm (average, 6 cm) in width. The largest flap was 22 cm × 6 cm and the smallest 6 cm × 3 cm. The length of the pedicle ranged from 2 cm to 10 cm (average, 8 cm). Skin defects of the donor site were covered by split-thickness skin grafts in 26 patients and direct closure in 1 patient. Twenty-six of 27 PIA flaps survived completely except venous congestion occurred in 1 patient, which led to necrosis of the distal 1/4 flap. Skin grafts over the donor sites survived completely without complications. The follow-up period ranged from 1 month to 2 years. Lipectomy or revision was performed in two patients because of scar contractures or bulkiness. The postoperative distance of the reconstructed web space was 6 cm on average. The reverse PIA flap is suited for defect cover in the treatment of severe contractures of the first web space. A usual pitfall using the reverse PIA flap is that the skin paddle is inadvertently outlined over the proximal 1 of 3 forearm to increase its distal reach, which usually leads to postoperative venous congestion. However, if the distal flap pole is placed at or distal to the midpoint from the lateral epicondyle to the radial side of the ulnar head, choosing the proximal 1 of 2 forearm as the donor site of the skin paddle to increase its distal reach is reliable.


Complexes of the outer mitochondrial membrane protein mitoNEET with resveratrol-3-sulfate.
Binding of the thiazolidinedione antidiabetic drug pioglitazone led to the discovery of a novel outer mitochondrial membrane protein of unknown function called mitoNEET. The protein is homodimeric and contains a uniquely ligated two iron-two sulfur cluster in each of its two cytosolic domains. Electrospray ionization mass spectrometry was employed to characterize solutions of the soluble cytosolic domain (amino acids 32--108) of the protein. Ions characteristic of dimers containing the cofactors were readily detected under native conditions. mitoNEET responded to exposure to solutions at low pH by dissociation to give monomers that retained the cofactor, followed by dissociation of the cofactor in a concerted fashion. mitoNEET formed complexes with resveratrol-3-sulfate, one of the primary metabolites of the natural product resveratrol. Resveratrol itself showed no tendency to interact with mitoNEET. The formation of complexes was evident in both electrospray ionization mass spectrometry and isothermal titration calorimetry measurements. Up to eight molecules of the compound associated with the dimeric form of the protein in a sequential fashion. Dissociation constants determined by micorcalorimetry were in the range 5-16 μM for the various binding sites. The only other known naturally occurring binding partner for mitoNEET at present is NADPH. It is very interesting that the iron-sulfur cluster containing protein interacts with two potentially redox active substances at the surface of mitochondria. These findings provide a new direction for research into two poorly understood, yet biomedically relevant, species.


Short-term pain control after palliative radiotherapy for uncomplicated bone metastases: a prospective cohort study.
This study aimed at evaluating the efficacy of different radiotherapy (RT) fractionation regimens in managing uncomplicated painful bone metastases (BM) and identifying predictive factors for pain control. Patients with 1 to 4 symptomatic BM from any primary solid tumors and a life expectancy exceeding 3 months were included in the study and received palliative RT, with SBRT restricted in the context of oligometastatic disease or in patients with good prognosis. Pain analysis using the Brief Pain Inventory (BPI) tool was conducted at baseline, 1 and 3 months after RT. Analgesic intake was recorded as morphine-equivalent doses (OME). Pain response was assessed using the International Consensus on Palliative Radiotherapy Endpoint (ICPRE). Multivariate logistic regression analyzed patient-related, tumor-related, and treatment-related factors predicting BM pain control at 3 months post-RT. From Feb 2022 to Feb 2023, 44 patients with 65 symptomatic BM were investigated. Breast (32%) and lung (24%) tumors were the most common primary tumors. Treatment plans included 3DCRT (60%) and VMAT (40%), with a median biological effective dose for tumors (BED) of 29 Gy [14-108]. All patients completed the 3-month follow-up. Pain response rates were 62% at 1 month and 60% at 3 months. Responders had better PS ECOG scores (67%; P = 0.008) and received active systemic therapies (67%: P = 0.036). Non-responders had lower pretreatment BPI (mean: 13.7 vs. 58.2; P = 0.032), with significantly higher values after 1 month (mean: 9.1 vs. 5.3, P = 0.033). Baseline BPI (OR: 1.17; 95% CI: 1.032-1.327; P = 0.014) and BPI at 1 month (OR: 0.83; 95% CI: 0.698-0.976; P = 0.025) were independent predictors of pain response at 3 months. Our findings show that palliative RT ensured short-term pain control in patients with BM, regardless of tumor type and dose-fractionation regimen. A larger sample size and a longer follow-up could potentially identify which patients are likely to benefit most from RT, and which fractionation might be indicated for achieving a durable pain relief. A multidisciplinary approach is paramount to provide a better care to BM patients.


"Down the Rabbit Hole" of Vaccine Misinformation on YouTube: Network Exposure Study.
Social media platforms such as YouTube are hotbeds for the spread of misinformation about vaccines. The aim of this study was to explore how individuals are exposed to antivaccine misinformation on YouTube based on whether they start their viewing from a keyword-based search or from antivaccine seed videos. Four networks of videos based on YouTube recommendations were collected in November 2019. Two search networks were created from provaccine and antivaccine keywords to resemble goal-oriented browsing. Two seed networks were constructed from conspiracy and antivaccine expert seed videos to resemble direct navigation. Video contents and network structures were analyzed using the network exposure model. Viewers are more likely to encounter antivaccine videos through direct navigation starting from an antivaccine video than through goal-oriented browsing. In the two seed networks, provaccine videos, antivaccine videos, and videos containing health misinformation were all found to be more likely to lead to more antivaccine videos. YouTube has boosted the search rankings of provaccine videos to combat the influence of antivaccine information. However, when viewers are directed to antivaccine videos on YouTube from another site, the recommendation algorithm is still likely to expose them to additional antivaccine information.


Lack of Casein Kinase 1 Delta Promotes Genomic Instability - The Accumulation of DNA Damage and Down-Regulation of Checkpoint Kinase 1.
Casein kinase 1 delta (CK1δ) is a conserved serine/threonine protein kinase that regulates diverse cellular processes. Mice lacking CK1δ have a perinatal lethal phenotype and typically weigh 30% less than their wild type littermates. However, the causes of death and small size are unknown. We observed cells with abnormally large nuclei in tissue from Csnk1d null embryos, and multiple centrosomes in mouse embryo fibroblasts (MEFs) deficient in CK1δ (MEFCsnk1d null). Results from γ-H2AX staining and the comet assay demonstrated significant DNA damage in MEFCsnk1d null cells. These cells often contain micronuclei, an indicator of genomic instability. Similarly, abrogation of CK1δ expression in control MEFs stimulated micronuclei formation after doxorubicin treatment, suggesting that CK1δ loss increases vulnerability to genotoxic stress. Cellular levels of total and activated checkpoint kinase 1 (Chk1), which functions in the DNA damage response and mitotic checkpoints, and its downstream effector, Cdc2/CDK1 kinase, were often decreased in MEFCsnk1d null cells as well as in control MEFs transfected with CK1δ siRNA. Hydroxyurea-induced Chk1 activation, as measured by Ser345 phosphorylation, and nuclear localization also were impaired in MEF cells following siRNA knockdown of CK1δ. Similar results were observed in the MCF7 human breast cancer cell line. The decreases in phosphorylated Chk1 were rescued by concomitant expression of siRNA-resistant CK1δ. Experiments with cycloheximide demonstrated that the stability of Chk1 protein was diminished in cells subjected to CK1δ knockdown. Together, these findings suggest that CK1δ contributes to the efficient repair of DNA damage and the proper functioning of mitotic checkpoints by maintaining appropriate levels of Chk1.


Use of a microscope stage-mounted Nickel-63 microirradiator for real-time observation of the DNA double-strand break response.
Eukaryotic cells begin to assemble discrete, nucleoplasmic repair foci within seconds after the onset of exposure to ionizing radiation. Real-time imaging of this assembly has the potential to further our understanding of the effects of medical and environmental radiation exposure. Here, we describe a microirradiation system for targeted delivery of ionizing radiation to individual cells without the need for specialized facilities. The system consists of a 25-micron diameter electroplated Nickel-63 electrode, enveloped in a glass capillary and mounted in a micromanipulator. Because of the low energy of the beta radiation and the minute total amount of isotope present on the tip, the device can be safely handled with minimum precautions. We demonstrate the use of this system for tracking assembly of individual repair foci in real time in live U2OS human osteosarcoma cells. Results indicate that there is a subset of foci that appear and disappear rapidly, before a plateau level is reached approximately 30 min post-exposure. This subset of foci would not have been evident without real-time observation. The development of a microirradiation system that is compatible with a standard biomedical laboratory expands the potential for real-time investigation of the biological effects of ionizing radiation.


Exploring the dynamics of research collaborations by mapping social networks in invasion science.
Moving towards more integrative approaches within the invasion sciences has been recognized as a means of improving linkages between science, policy, and practice. Yet despite the recognition that biological invasions pose complex social-ecological challenges, the invasion literature poorly covers social-ecological or distinctly integrative research. Various initiatives and investments have been made towards building research capacity and conducting more integrative research aimed at improving the management of biological invasions. Using a combination of social network and thematic analysis approaches, and the South African Working for Water (WfW) program as a case study for the management of invasive species, we identify and explore the roles of core authors in shaping collaboration networks and research outputs, based on bibliographic records. We found that research produced under the auspices of WfW is authored by a handful of core authors, conducting primarily ecologically-focused research, with social research significantly underrepresented. Core authors identified in this study play an essential role in mediating relationships between researchers, in addition to potentially controlling access to those seeking to form collaborations, maintaining network cohesion and connectivity across institutional and disciplinary boundaries. Research projects should be designed to span disciplines and institutions if they are to adequately address complex challenges.


SOX17 Regulates Conversion of Human Fibroblasts Into Endothelial Cells and Erythroblasts by Dedifferentiation Into CD34+ Progenitor Cells.
The mechanisms underlying the dedifferentiation and lineage conversion of adult human fibroblasts into functional endothelial cells have not yet been fully defined. Furthermore, it is not known whether fibroblast dedifferentiation recapitulates the generation of multipotent progenitors during embryonic development, which give rise to endothelial and hematopoietic cell lineages. Here we established the role of the developmental transcription factor SOX17 in regulating the bilineage conversion of fibroblasts by the generation of intermediate progenitors. CD34+ progenitors were generated after the dedifferentiation of human adult dermal fibroblasts by overexpression of pluripotency transcription factors. Sorted CD34+ cells were transdifferentiated into induced endothelial cells and induced erythroblasts using lineage-specific growth factors. The therapeutic potential of the generated cells was assessed in an experimental model of myocardial infarction. Induced endothelial cells expressed specific endothelial cell surface markers and also exhibited the capacity for cell proliferation and neovascularization. Induced erythroblasts expressed erythroid surface markers and formed erythroid colonies. Endothelial lineage conversion was dependent on the upregulation of the developmental transcription factor SOX17, whereas suppression of SOX17 instead directed the cells toward an erythroid fate. Implantation of these human bipotential CD34+ progenitors into nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice resulted in the formation of microvessels derived from human fibroblasts perfused with mouse and human erythrocytes. Endothelial cells generated from human fibroblasts also showed upregulation of telomerase. Cell implantation markedly improved vascularity and cardiac function after myocardial infarction without any evidence of teratoma formation. Dedifferentiation of fibroblasts to intermediate CD34+ progenitors gives rise to endothelial cells and erythroblasts in a SOX17-dependent manner. These findings identify the intermediate CD34+ progenitor state as a critical bifurcation point, which can be tuned to generate functional blood vessels or erythrocytes and salvage ischemic tissue.


Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice.
To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial structure and function, we have produced mice expressing altered forms of this sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in which the cardiac myosin heavy chain-binding and titin-binding domain has been replaced with novel amino acid residues. Analogous heterozygous defects in humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the mutated MyBP-C alleles express less than 10% of truncated protein in M-bands of otherwise normal sarcomeres. Homozygous mice bearing mutated MyBP-C alleles are viable but exhibit neonatal onset of a progressive dilated cardiomyopathy with prominent histopathology of myocyte hypertrophy, myofibrillar disarray, fibrosis, and dystrophic calcification. Echocardiography of homozygous mutant mice showed left ventricular dilation and reduced contractile function at birth; myocardial hypertrophy increased as the animals matured. Left-ventricular pressure-volume analyses in adult homozygous mutant mice demonstrated depressed systolic contractility with diastolic dysfunction. These data revise our understanding of the role that MyBP-C plays in myofibrillogenesis during cardiac development and indicate the importance of this protein for long-term sarcomere function and normal cardiac morphology. We also propose that mice bearing homozygous familial hypertrophic cardiomyopathy-causing mutations may provide useful tools for predicting the severity of disease that these mutations will cause in humans.


System efficiency of a tap transformer based grid connection topology applied on a direct driven generator for wind power.
Results from experiments on a tap transformer based grid connection system for a variable speed vertical axis wind turbine are presented. The tap transformer based system topology consists of a passive diode rectifier, DC-link, IGBT inverter, LCL-filter, and tap transformer. Full range variable speed operation is enabled by using the different step-up ratios of a tap transformer. Simulations using MATLAB/Simulink have been performed in order to study the behavior of the system. A full experimental set up of the system has been used in the laboratory study, where a clone of the on-site generator was driven by an induction motor and the system was connected to a resistive load to better evaluate the performance. Furthermore, the system is run and evaluated for realistic wind speeds and variable speed operation. For a more complete picture of the system performance, a case study using real site Weibull parameters is done, comparing different tap selection options. The results show high system efficiency at nominal power and an increase in overall power output for full tap operation in comparison with the base case, a standard transformer. In addition, the loss distribution at different wind speeds is shown, which highlights the dominant losses at low and high wind speeds. Finally, means for further increasing the overall system efficiency are proposed.


Facial erysipelas in the immunocompromised host. Report of two cases.
Two cases of facial erysipelas in immunologically altered hosts are reported herein. The unusual presentation with absence of erythema in the skin lesion is emphasized. Atypical fever patterns were also noted. In one patient, the facial lesion followed the onset of fever by 48 hours, and, in the other, the facial swelling preceded the fever. Various aspects of the patient's altered host status are discussed in light of the atypical clinical presentation. Recognition of facial erysipelas as a potential source of group A beta-hemolytic streptococcemia in immune-altered hosts is important to ensure rapid and appropriate therapeutic intervention.


Postictal generalized EEG suppression is linked to seizure-associated respiratory dysfunction but not postictal apnea.
The relationship of postictal generalized electroencephalography (EEG) suppression (PGES) with sudden unexpected death in epilepsy (SUDEP) is controversial. It has been suggested that PGES is associated with respiratory inhibition leading to SUDEP, but the relationship between PGES and respiratory depression is unknown. Respiratory rate and amplitude of airflow increase following seizures but there is persistent hypercapnia and hypoxemia. To determine whether seizures with PGES result in respiratory dysfunction, we analyzed respiratory parameters recorded during video-EEG telemetry in patients with localization-related epilepsy. Secondarily generalized convulsive seizures (GC) with PGES on scalp EEG or bilateral postictal attenuation (BA) on intracranial recordings were compared to GC without PGES/BA. Oxygen desaturation nadir and duration, end-tidal CO(2) (ETCO(2) ), apnea duration, and duration of the seizure and of the convulsive component were compared in GC with or without PGES/BA. There was no significant difference between GC with (n = 30) or without PGES/BA (n = 72) for total seizure duration or duration of the convulsion. GC with PGES/BA had a mean oxygen desaturation nadir of 68.8 ± 11.8% (71.5, 43-88) (mean ± standard deviation [median, range]) that was lower (p = 0.002) than seizures without PGES/BA (76.31 ± 10.17% [79, 42-93]). The duration of desaturation was significantly longer and peak ETCO(2) higher in GC with PGES/BA. There was no difference in apnea duration. Apnea did not start during PGES/BA and did not typically extend into the postictal period in GC with or without PGES/BA. PGES is not associated with postictal central apnea but is more likely related to the severity of seizure-associated intrinsic pulmonary dysfunction.


Reducing racial bias in SpO2 estimation: The effects of skin pigmentation.
Accurate pulse-oximeter readings are critical for clinical decisions, especially when arterial blood-gas tests - the gold standard for determining oxygen saturation levels - are not available, such as when determining COVID-19 severity. Several studies demonstrate that pulse oxygen saturation estimated from photoplethysmography (PPG) introduces a racial bias due to the more profound scattering of light in subjects with darker skin due to the increased presence of melanin. This leads to an overestimation of blood oxygen saturation in those with darker skin that is increased for low blood oxygen levels and can result in a patient not receiving potentially life-saving supplemental oxygen. This racial bias has been comprehensively studied in conventional finger pulse oximetry but in other less commonly used measurement sites, such as in-ear pulse oximetry, it remains unexplored. Different measurement sites can have thinner epidermis compared with the finger and lower exposure to sunlight (such as is the case with the ear canal), and we hypothesise that this could reduce the bias introduced by skin tone on pulse oximetry. To this end, we compute SpO2 in different body locations, during rest and breath-holds, and compare with the index finger. The study involves a participant pool covering 6-pigmentation categories from Fitzpatrick's Skin Pigmentation scale. These preliminary results indicate that locations characterized by cartilaginous highly vascularized tissues may be less prone to the influence of melanin and pigmentation in the estimation of SpO2, paving the way for the development of non-discriminatory pulse oximetry devices.


Low expression of the X-linked ribosomal protein S4 in human serous epithelial ovarian cancer is associated with a poor prognosis.
The X-linked ribosomal protein S4 (RPS4X), which is involved in cellular translation and proliferation, has previously been identified as a partner of the overexpressed multifunctional protein YB-1 in several breast cancer cells. Depletion of RPS4X results in consistent resistance to cisplatin in such cell lines. As platinum-based chemotherapy is a standard first line therapy used to treat patients with ovarian cancer, we evaluated the prognostic value of RPS4X and YB-1 at the protein level in specimen from 192 high-grade serous epithelial ovarian cancer patients. Immunohistochemistry studies indicated that high expression of RPS4X was associated with a lower risk of death and later disease progression (HR = 0.713, P = 0.001 and HR = 0.761, P = 0.001, respectively) as compared to low expression of RPS4X. In contrast, YB-1 was not significantly associated with either recurrence or survival time in this cohort. Finally, the depletion of RPS4X with different siRNAs in two different ovarian cancer cell lines reduced their proliferative growth rate but more importantly increased their resistance to cisplatin. Altogether, these results suggest that the levels of RPS4X could be a good indicator for resistance to platinum-based therapy and a prognostic marker for ovarian cancer. Our study also showed that RPS4X is an independent prognostic factor in patients with serous epithelial ovarian cancer.


Characterisation of the expression of NMDA receptors in human astrocytes.
Astrocytes have long been perceived only as structural and supporting cells within the central nervous system (CNS). However, the discovery that these glial cells may potentially express receptors capable of responding to endogenous neurotransmitters has resulted in the need to reassess astrocytic physiology. The aim of the current study was to characterise the expression of NMDA receptors (NMDARs) in primary human astrocytes, and investigate their response to physiological and excitotoxic concentrations of the known endogenous NMDAR agonists, glutamate and quinolinic acid (QUIN). Primary cultures of human astrocytes were used to examine expression of these receptors at the mRNA level using RT-PCR and qPCR, and at the protein level using immunocytochemistry. The functionality role of the receptors was assessed using intracellular calcium influx experiments and measuring extracellular lactate dehydrogenase (LDH) activity in primary cultures of human astrocytes treated with glutamate and QUIN. We found that all seven currently known NMDAR subunits (NR1, NR2A, NR2B, NR2C, NR2D, NR3A and NR3B) are expressed in astrocytes, but at different levels. Calcium influx studies revealed that both glutamate and QUIN could activate astrocytic NMDARs, which stimulates Ca2+ influx into the cell and can result in dysfunction and death of astrocytes. Our data also show that the NMDAR ion channel blockers, MK801, and memantine can attenuate glutamate and QUIN mediated cell excitotoxicity. This suggests that the mechanism of glutamate and QUIN gliotoxicity is at least partially mediated by excessive stimulation of NMDARs. The present study is the first to provide definitive evidence for the existence of functional NMDAR expression in human primary astrocytes. This discovery has significant implications for redefining the cellular interaction between glia and neurons in both physiological processes and pathological conditions.


Modeling of cell culture damage and recovery leads to increased antibody and biomass productivity in CHO cell cultures.
The development of an efficient and productive cell-culture process requires a deep understanding of intracellular mechanisms and extracellular conditions for optimal product synthesis. Mathematical modeling provides an effective strategy to predict, control, and optimize cell performance under a range of culture conditions. In this study, a mathematical model is proposed for the investigation of cell damage of a Chinese hamster ovary cell culture secreting recombinant anti-RhD monoclonal antibody (mAb). Irreversible cell damage was found to be correlated with a reduction in pH. This irreversible damage to cellular function is described mathematically by a Tessier-based model, in which the actively growing fraction of cells is dependent on an intracellular metabolic product acting as a growth inhibitor. To further verify the model, an offline model-based optimization of mAb production in the cell culture was carried out, with the goal of minimizing cell damage and thereby enhancing productivity through intermittent refreshment of the culture medium. An experimental implementation of this model-based strategy resulted in a doubling of the yield as compared to the batch operation and the resulting biomass and productivity profiles agreed with the model predictions.


Robot-assisted surgery: an emerging platform for human neuroscience research.
Classic studies in human sensorimotor control use simplified tasks to uncover fundamental control strategies employed by the nervous system. Such simple tasks are critical for isolating specific features of motor, sensory, or cognitive processes, and for inferring causality between these features and observed behavioral changes. However, it remains unclear how these theories translate to complex sensorimotor tasks or to natural behaviors. Part of the difficulty in performing such experiments has been the lack of appropriate tools for measuring complex motor skills in real-world contexts. Robot-assisted surgery (RAS) provides an opportunity to overcome these challenges by enabling unobtrusive measurements of user behavior. In addition, a continuum of tasks with varying complexity-from simple tasks such as those in classic studies to highly complex tasks such as a surgical procedure-can be studied using RAS platforms. Finally, RAS includes a diverse participant population of inexperienced users all the way to expert surgeons. In this perspective, we illustrate how the characteristics of RAS systems make them compelling platforms to extend many theories in human neuroscience, as well as, to develop new theories altogether.


Overcoming Endocytosis Deficiency by Cubosome Nanocarriers.
The use of lipid-based nanoparticles for the delivery of biomacromolecules has attracted considerable attention due to the current interest in protein-based therapeutics. Cubosomes protect the incorporated therapeutics, which are susceptible to degradation by enzymes, thereby improving their bioavailability, and concomitantly enhance cellular uptake. The cubosome nanoparticles presented herein were loaded with bovine serum albumin (BSA) and characterized by small-angle X-ray scattering and dynamic light scattering techniques, while the BSA encapsulation and its release were evaluated in vitro. The ability of this formulation to increase the cellular uptake of albumin by 2-fold was tested on various types of renal tubular cells and confirmed by in vivo renal uptake experiments in mice. The obtained results show that cubosomes are able to deliver BSA inside the cell through distinct uptake and intracellular routing. These data were substantiated, with evidence of a high cubosome-mediated uptake of BSA in Clcn5 knockout mice characterized by defective receptor-mediated endocytosis. The use of cubosomes as a delivery system thus represents a promising approach to overcome the low endocytic uptake in diseased epithelial cells and to treat dysfunctions of the kidney proximal tubule.


Complex foraging polymorphism in bluegill sunfish.
The bluegill sunfish (Lepomis macrochirus) is considered a generalist predator, adept at feeding in both the littoral and open-water habitats of North American freshwater lakes. We demonstrate adaptive intraspecific variation in morphology and foraging behaviors within single lakes. This variation appears to make individual fish specialized for feeding in either the littoral or open-water habitat. Discovery of a complex polymorphism in such a well-studied species suggests that adaptive variation may be more common than is currently perceived.


Tamoxifen use for the management of mania: a review of current preclinical evidence.
Preliminary data on the efficacy of tamoxifen in reducing manic symptoms of bipolar disorder (BD) suggest that this agent may be a potential treatment for the management of this psychiatric disorder. However, the antimanic properties of tamoxifen have not been fully elucidated, hampering the development and/or use of mood-stabilising drugs that may share its same therapeutic mechanisms of action. Notably, we may gain a greater understanding of the neurobiological and therapeutic properties of tamoxifen by using suitable animal models of mania. Here, we review the preclinical studies that have evaluated the effects of tamoxifen to provide an overview of the current progress in our understanding of its antimanic actions, highlighting the critical role of protein kinase C (PKC) as a therapeutic target for the treatment of BD. To date, this field has struggled to make significant progress, and the organisation of an explicit battery of tests is a valuable tool for assessing a number of prominent facets of BD, which may provide a greater understanding of the entire scope of this disease.


OCT ANGIOGRAPHY, VISUAL FIELD AND RNFL WITH VARIOUS MEDICATIONS IN HYPERTENSIVE GLAUCOMAS.
The aim of the study was to determine whether hypertensive glaucoma (HTG) with different types of treatment leads to significant damage in any of the evaluated parameters. The sample, consisting of 36 HTG patients (72 eyes), was divided into three subgroups: In the first group, patients were treated with combination therapy (latanoprost + timolol, latanoprost + dorzolamide + timolol, dorzolamide + timolol). The group consisted of seven women and five men, with an average age of 64 years (49-81). In the second group, patients were treated with beta-blockers (carteolol, betaxolol, timolol). The group consisted of five women and five men, with an average age of 62 years (27-77). In the third group, patients were treated with prostaglandins (latanoprost, bimatoprost). The group consisted of eleven women and three men, with an average age of 61 years (61-78). Criteria for inclusion in the study were visual acuity of 1.0 with a possible correction of less than ±3 dioptres, approximately the same changes in the visual fields of all patients, an intraocular pressure (IOP) of less than 18 mmHg, and no other ocular or neurological disease. The retinal nerve fibre layer (RNFL) on the optic nerve target and vessel density (VD) was measured using an Avanti RTVue XR from Optovue. We determined the values of VD in whole image (WI) and VD of peripapillary (PP). In both cases, we then measured all vessels (VDa) and small vessels (VDs). The visual field was examined by means of a fast threshold glaucoma program with a Medmont M 700 instrument. In addition to the sum of sensitivities in apostilbs (asb) in the range of 0-22 degrees, the overall visual field defect (OD) was also evaluated. The statistical analysis was carried out using a multivariate regression model with adjustment for age and gender. The measured values of the third group were taken as baseline. In the statistical analysis, we have found differences in visual field in the combination treatment group (p = 0.0006) and differences were recorded for RNFL in the beta-blocker group (p = 0.04).


Pet ownership is associated with increased risk of non-atopic asthma and reduced risk of atopy in childhood: findings from a UK birth cohort.
Studies have shown an inverse association of pet ownership with allergy but inconclusive findings for asthma. To investigate whether pet ownership during pregnancy and childhood was associated with asthma and atopy at the age of 7 in a UK population-based birth cohort. Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used to investigate associations of pet ownership at six time points from pregnancy to the age of 7 with asthma, atopy (grass, house dust mite, and cat skin prick test) and atopic vs. non-atopic asthma at the age of 7 using logistic regression models adjusted for child's sex, maternal history of asthma/atopy, maternal smoking during pregnancy, and family adversity. A total of 3768 children had complete data on pet ownership, asthma, and atopy. Compared with non-ownership, continuous ownership of any pet (before and after the age of 3) was associated with 52% lower odds of atopic asthma [odds ratio (OR) 0.48, 95% CI 0.34-0.68]. Pet ownership tended to be associated with increased risk of non-atopic asthma, particularly rabbits (OR 1.61, 1.04-2.51) and rodents (OR 1.86, 1.15-3.01), comparing continuous vs. non-ownership. Pet ownership was consistently associated with lower odds of sensitization to grass, house dust mite, and cat allergens, but rodent ownership was associated with higher odds of sensitization to rodent allergen. Differential effects of pet ownership on atopic vs. non-atopic asthma were evident for all pet types. Pet ownership during pregnancy and childhood in this birth cohort was consistently associated with a reduced risk of aeroallergen sensitization and atopic asthma at the age of 7, but tended to be associated (particularly for rabbits and rodents) with an increased risk of non-atopic asthma. The opposing effects on atopy vs. non-atopic asthma might be considered by parents when they are deciding whether to acquire a pet.


Fibreoptic endoscopy and the use of the Sengstaken tube in acute gastrointestinal haemorrhage in patients with portal hypertension and varices.
The value of emergency upper gastrointestinal fibre-endoscopy, followed where required by the use of a modified Sengstaken tube, was studied during 84 episodes of acute bleeding in 75 patients who had evidence of portal hypertension with varices. The portal hypertension was due to alcoholic cirrhosis in 80% and to cryptogenic cirrhosis in 9% of the patients. By definition, varices were present in all patients, but in only 66% of episodes were the varices the cause of the bleed. The correct diagnosis of the source of bleeding was made at endoscopy in 89%. A Boyce modification of the Sengstaken-Blakemore tube was passed in 73% of the episodes of variceal bleeding. It effectively stopped the bleeding primarily in 85% of patients but was successful as a final definitive measure only in 46%. Furthermore, only 40% of the patients in whom the tube was passed, survived. Mortality rate could be related to the severity of the bleed and to hepatocellular dysfunction. Survival increased from 23% in those patients with jaundice, ascites, and encephalopathy on admission to 92% in those without these manifestations. The in-hospital survival rate was 52% in patients bleeding from varices and 64% in those bleeding from other causes, with an overall survival rate of 56%, indicating the poor prognosis in cirrhotic patients with gastrointestinal bleeding, irrespective of the cause.


meta-Cleavage of hydroxynaphthoic acids in the degradation of phenanthrene by Sphingobium sp. strain PNB.
Polycyclic aromatic hydrocarbons (PAHs) comprise a group of priority organic pollutants that are toxic and/or carcinogenic. Phenanthrene, the simplest PAH among recognized priority pollutants, is commonly used as a model compound for the study of PAH biodegradation. Sphingobium sp. strain PNB, capable of degrading phenanthrene as a sole carbon and energy source, was isolated from a municipal waste-contaminated soil sample. A combination of chromatographic and spectrometric analyses, together with oxygen uptake and enzyme activity studies, suggested the presence of phenanthrene degradation pathways in this strain. Identification of metabolites suggested that initial dioxygenation of phenanthrene took place at both 3,4- and 1,2-carbon positions; meta-cleavage of resultant diols led to the formation of 1-hydroxy-2-naphthoic acid and 2-hydroxy-1-naphthoic acid, respectively. The hydroxynaphthoic acids, in turn, were metabolized by a meta-cleavage pathway(s), leading to the formation of 2,2-dicarboxychromene and 2-hydroxychromene-2-glyoxylic acid, respectively. These metabolites were subsequently transformed to catechol via salicylic acid, which further proceeds towards the tricarboxylic acid cycle leading to complete mineralization of the compound phenanthrene. The present study establishes the metabolism of hydroxynaphthoic acids by a meta-cleavage pathway in the degradation of phenanthrene, expanding our current understanding of microbial degradation of PAHs.


Cardiac dysautonomia in lepromatous leprosy.
Cardiovascular autonomic functions were studied in 32 patients of lepromatous leprosy, including 12 patients of lepra reaction. Fifty age and sex matched healthy subjects served as controls. Variable degree of autonomic dysfunction was observed in the study group. The derangement of autonomic functions in patients of leprosy can be explained on the basis of neurotrophic action of lepra bacilli that infiltrate the sympathetic and the parasympathetic fibres.


Vitamin D receptor gene start codon polymorphisms (FokI) and bone mineral density: interaction with age, dietary calcium, and 3'-end region polymorphisms.
Osteoporosis is a polygenic disease, whose determining loci have not yet been identified. Vitamin D receptor (VDR) gene polymorphisms in the 3'-end region (as determined by the enzymes BsmI and ApaI) have been inconsistently associated with bone mineral mass. More recently, VDR start codon polymorphisms (as determined by the enzyme FokI) have been found to be related to adult bone mineral density (BMD) in pre- and postmenopausal American women. We investigated the association between BMD and FokI genotypes in premenopausal European-Caucasian women as well as in prepubertal girls from the same genetic background and examined the interaction with VDR 3'-end region polymorphisms and with dietary calcium intake. Areal BMD (g/cm2) was measured by dual-energy X-ray absorptiometry at the level of the lumbar spine, femoral neck, and femoral shaft in 177 healthy premenopausal women (age range, 18.7-56.0 years) as well as in 155 prepubertal girls (age range, 6.6-11.4 years). Genotyping for FokI, BsmI, and ApaI VDR polymorphisms was performed using polymerase chain reaction methods. FokI genotype-dietary calcium interaction was cross-sectionally analyzed in all subjects and longitudinally in 103 prepubertal girls enrolled in a calcium intervention trial. The prevalence of FokI VDR gene polymorphisms in this cohort was 15% for ff, 50% for Ff, and 35% for FF. In the whole cohort of premenopausal women or prepubertal girls, no significant association was found between FokI VDR gene polymorphisms and BMD, even adjusted for age (Z score), weight, height, and calcium intake. Further analysis of FokI VDR gene polymorphisms and dietary calcium intake suggested a possible interaction in BMD determination, since a trend for an association with FokI genotypes was more evident at high than low calcium intake in both cross-sectional and longitudinal studies. Furthermore, cross-genotyping FokI and either BsmI or ApaI VDR polymorphisms suggested that the ff genotype was associated with a significantly lower lumbar spine BMD in bb and aa prepubertal girls. FokI VDR gene polymorphisms were not significantly associated with BMD in healthy European-Caucasian females. However, cross-genotyping of the VDR 3'-end and start codon polymorphic regions may provide a further insight into the complex determination of BMD.


Promoting children's health and well-being: broadening the therapy perspective.
Physical activity is essential to promote children's health and well-being. Increased sedentary behavior in children is a factor contributing to the escalation in childhood obesity in the general population. Clinical conditions, particularly physical disabilities, which reduce physical activity, may also lead to a higher risk of being overweight or obese. This paper reviews physical activity and sedentary behavior and illustrates how habitual (daily) physical activity, motor performance, and the capacity to be active are distinct and important aspects of a child's activity behavior. Positive health outcomes are linked to achieving adequate habitual levels of physical activity. This paper also highlights how pediatric therapists can promote health for those children who are already overweight or obese or are at higher risk of being overweight or obese. Physical and occupational therapists are encouraged to embrace a broad perspective of physical activity and extend children's therapeutic and health-promotion programs to include assessment of habitual level of physical activity and sedentary behavior, and promotion of recommended levels of daily physical activity. This role can also be extended beyond the area of disability.


Isoquinoline alkaloids and their binding with polyadenylic acid: potential basis of therapeutic action.
After fifty years of DNA targeting through intercalators and groove binders and related studies now the current focus is in RNA targeting. Polyadenylic acid [poly(A)] tail of mRNA has been recently established as a potential drug target due to its significant role in the initiation of translation, maturation and stability of mRNA as well as in the production of alternate proteins in eukaryotic cells. Isoquinoline group of alkaloids have their importance in contemporary biomedical research and drug discovery programme due to extensive pharmacological and biological activity. Very recently some small molecule alkaloids of the isoquinoline group have been found to bind poly(A) with remarkably high affinity leading to self structure formation. The alkaloids have a high binding affinity towards single stranded poly(A) whereas their binding with double stranded poly(A) is weak. Among the alkaloids discussed here, berberine and coralyne are found to be capable to induce self-structure in poly(A). All the binding phenomena are characterized by electrostatic interaction between RNA and the alkaloids and the mode of binding revealed as full or partial intercalation. This review focuses on the structural and biological significance of poly(A) and the recent developments in the use of plant alkaloids and their synthetic analogs to control the structure and function of this RNA for the development of new alkaloid based molecules specifically targeted to poly(A) structures.


Behavior Modification of Nanostructured PbO₂ Electrodes in Lead Acid Batteries Changing Electrolyte Concentration and Separator.
Currently, lead acid battery is extensively investigated owing to its prevalent use as a startinglighting and ignition device. An essential role for electrochemical reactions is played by the surface area available for conversion reactions and a possible approach is the use of nanostructured electrodes. In this work, lead dioxide nanostructured electrodes were tested in order to investigate the dependence of the charge and discharge behaviour on some parameters such as electrolyte concentration, and a new type of thin separator. In this last case, it is possible to reduce the size of the cell by using a very thin separator comparable to the nanostructured electrode thickness. Besides, a low concentration of electrolyte was also tested for studying its influence on the performance of a nanostructured electrode. Lead dioxide electrodes were cycled at 1C-rate and discharged to a cutoff voltage of 1.2 V up to 90% of the gravimetric capacity. Electrodes were assembled in a zero gap configuration using a commercial negative plate as counter-electrode with a large excess of active mass in comparison to the nanostructured one. Tests were conducted in very stressful conditions, in order to compare the behaviour of this new type of battery with that of the commercial one.


The brown adipose cell: a unique model for understanding the molecular mechanism of insulin resistance.
Type 2 diabetes mellitus (NIDDM) is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signaling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue (BAT) and pinpoints the role of BAT in the control of glucose homeostasis.


Dopamine D2 Receptor-Mediated Modulation of Rat Retinal Ganglion Cell Excitability.
Ganglion cells (RGCs) are the sole output neurons of the retinal circuity. Here, we investigated whether and how dopamine D2 receptors modulate the excitability of dissociated rat RGCs. Application of the selective D2 receptor agonist quinpirole inhibited outward K+ currents, which were mainly mediated by glybenclamide- and 4-aminopyridine-sensitive channels, but not the tetraethylammonium-sensitive channel. In addition, quinpirole selectively enhanced Nav1.6 voltage-gated Na+ currents. The intracellular cAMP/protein kinase A, Ca2+/calmodulin-dependent protein kinase II, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathways were responsible for the effects of quinpirole on K+ and Na+ currents, while phospholipase C/protein kinase C signaling was not involved. Under current-clamp conditions, the number of action potentials evoked by positive current injection was increased by quinpirole. Our results suggest that D2 receptor activation increases RGC excitability by suppressing outward K+ currents and enhancing Nav1.6 currents, which may affect retinal visual information processing.


Health systems, quality of health care, and translational cancer research: the role of the Istituto Superiore Sanità - Rome.
Faced with the challenge of ensuring high-quality and cost-effective health systems in the context of persistent financial crisis, a global strategy for cancer prevention and treatment represents a priority for public health bodies and governments. The key goals for the initiative are to define standards of cancer prevention and care while leveraging the continuous progress of biomedical research in the interest of public health. In Italy, the establishment of a network of Comprehensive Cancer Centres (CCC) named the Alliance Against Cancer (ACC) is an important initiative taken by the Ministry of Health to foster common strategies for enhancing the quality of oncology research and care at the national level. The Istituto Superiore di Sanità (ISS) has played an important role in supporting ACC activities through a special national program called ISS for ACC, launched by the Italian Ministry of Health in 2006. A similar role has been pursued in subsequent initiatives, including ISS support for a project aimed at providing international accreditation of the CCC of the ACC, funded by the Italian Ministry of Health. The results of this initiative, reported in the current issue of Tumori, are especially significant since specific indicators of quality for research and cancer care have been successfully defined for all the participating institutes. As the leading technical and scientific body of the Italian National Health Service, the ISS will continue to play a proactive role in supporting national networks and strategic national and international initiatives aimed at promoting public health.


Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism.
Artemisinin (ART)-based combination therapies (ACTs) are the first-line drugs-and often the last treatments-that can effectively cure Plasmodium falciparum infections. Unfortunately, the decreased clinical efficacy of artesunate, one of the major ART derivatives, was recently reported along the Thailand-Cambodia border. Through long-term artemisinin pressure in vitro, we have obtained an ART-tolerant strain that can survive extremely high doses of ART. We showed that drug pressure could induce a subpopulation of ring stages into developmental arrest, which can explain the ART tolerance in P. falciparum. We also observed interesting transcriptomic modifications possibly associated with the acquisition of ART tolerance. These modifications include the overexpression of heat shock and erythrocyte surface proteins and the downexpression of a cell cycle regulator and a DNA biosynthesis protein. This study highlights a new phenomenon in the Plasmodium response to ART that may explain the delayed clearance of parasites after artesunate treatment observed on the Thailand-Cambodia border and that provides important information for achieving a better understanding of the mechanisms of antimalarial resistance.


One-pot native chemical ligation of peptide hydrazides enables total synthesis of modified histones.
One of the rising demands in the field of protein chemical synthesis is the development of facile strategies that yield the protein in workable quantities and homogeneity, with fewer handling steps. Although the native chemical ligation of peptide hydrazides has recently been shown to be useful for the chemical synthesis of proteins carrying acid-sensitive modification groups, previous hydrazide-based protein synthesis studies have used sequential ligation strategies. Here, we report a practical method for a "one-pot" native chemical ligation of peptide hydrazides that would circumvent the need for the isolation of the intermediate products. This method employed a fast and selective arylboronate oxidation reaction mediated by H2O2, which draws attention to the potential applications of the thus far under-exploited boron-based functionalities in protein chemical synthesis. To demonstrate the practicality and efficiency of the new one-pot method, we report its application to a scalable total synthesis of modified histones (with five analogues of H3 and H4 as examples) on a multi-milligram scale, with good homogeneity.


Comparative metabolism of copper.
Copper is required in trace amounts for many body functions. The prominent effects of Cu deficiency or Cu toxicosis differs greatly between animal species. Along with iron, Cu is necessary for the transfer of O2 via a cascade of enzymes so that energy may be available for vital body functions without overheating of the tissues through rapid oxidation. As a part of lysyl oxidase, Cu has an obligate function in the maturation of all connective tissue (including elastic tissue and bone) maintaining the form and integrity of all body organs. As a constituent of tyrosinase, Cu is involved in the formation of melanin, thus preventing albinism. Copper also is involved in the myelination of nerve fibers and the production of neutrophils, enkephalins, lipoproteins, and cholesterol. Copper must be properly sequestered to prevent toxicosis. Copper is stored primarily as metallothioneins and as superoxide dismutase and is transported primarily as ceruloplasmin or as low molecular weight proteins, peptides, and amino acids.


[Correlation between preoperative MRI measurement of cross-sectional area of hamstring tendon and graft in anterior cruciate ligament reconstruction].
To study the corretation between the cross-sectional area of hamstring tenden measured by MRI and gragt in anterior cruciate ligament rexonstruction. MRI data of 50 patients who planned to undergo anterior cruciate ligament reconstruction from November 2021 to March 2022 were collected, including 32 males and 18 females, aged from 19 to 48 years old with an average of(31.1±8.7) years. Before the operation, the semitendinosus and gracilis tendons were measured and recorded by MRI, and then the anterior cruciate ligament was reconstructed under arthroscope. During the operation, gracilis and semitendinosus tendons were taken to prepare the final tendon to be transplanted, and the diameter of the prepared final graft was measured during the operation. Finally, the data were analyzed by statistical software. The cross sectional areas of semitendinosus tendon, gracilis tendon, semitendinosus tendon and gracilis tendon measured by MRI were significantly and positively correlated with the diameter of grafts required in anterior cruciate ligament surgery, the r values were 0.858, 0.728, 0.842(P<0.001), respectively. The area under curre (AUC), sensitivity, and specificity of the sum of the cross sectional areas of semitendinosus tendon and gracilis tendon were 0.925, 90.48%, and 85.71%, respectively. In patients undergoing anterior cruciate ligament reconstruction, preoperative MRI measurement has a strong statistical correlation with the diameter of hamstring muscle transplantation during operation. The sum of the cross sectional areas of semitendinosus tendon and gracilis tendon has a high predictive value for the diameter of grafts during anterior cruciate ligament reconstruction, and can predict the size of grafts during operation.


Emergency medicine in the wilderness. Part Two.
The guiding tenet of field trauma, as in all of medical or dental treatment, is "first, do no harm". A common sense approach to the whole patient followed by a careful examination of the area of injury will provide outstanding outcome. A few simple techniques of wound care judiciously applied will likewise provide an opportunity for excellent functional status.


Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenström's macroglobulinemia, and mantle-cell lymphoma.
Fludarabine phosphate (F-AMP) has significant activity in follicular lymphoma and in B-cell chronic lymphatic leukemia, where it has demonstrated high complete response (CR) rates. Lymphoplasmacytoid (LPC) lymphoma, Waldenstrom's macroglobulinemia (WM), and mantle-cell lymphoma (MCL) also present with advanced-stage disease and are incurable with standard alkylator-based chemotherapy. A phase II trial was undertaken to determine the activity of F-AMP in patients newly diagnosed with these diseases. Between 1992 and 1996, 78 patients (aged 18 to 75 years) received intravenous F-AMP (25 mg/m2/d for 5 days, every 4 weeks) until maximum response, plus two further cycles as consolidation. The primary end point was response rate; secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Forty-four (62%) of 71 assessable patients had a response to F-AMP (LPC lymphoma, 63%; WM, 79%; MCL, 41%); the CR rate was 15%. At a median follow-up of 1.5 years, 19 of 44 responding patients have had progression of lymphoma; the median duration of response was 2.5 years. The median survival has not yet been reached. There was no significant difference in the duration of response or OS between patients with different histologies; TTP was shorter in patients with MCL (P = .015). Myelosuppression was relatively common, and the treatment-related mortality (TRM) was 5%, mostly associated with pancytopenia and infection. Single-agent fludarabine phosphate is active in previously untreated LPC lymphoma and WM, with only moderate activity in MCL. However, the CR rate is low, and the TRM is relatively high. Its role in combination chemotherapy remains to be demonstrated.


Arsenic in seafood is associated with increased thyroid-stimulating hormone (TSH) in healthy volunteers - A randomized controlled trial.
Exposure to exogenous elements like arsenic (As) may influence thyroid enzymes, thyroid-stimulating hormone (TSH), and the two principal thyroid hormones, free thyroxine (FT4) and free triiodothyronine (FT3), but little is known about how this is related to organic arsenicals, the main form in seafood. To investigate whether a high intake of dietary arsenic from seafood can impact thyroid function and thyroid hormones by examining possible associations with changes in TSH, FT4, FT3 and the FT4:FT3-ratio in plasma. Thirty-eight healthy subjects were randomized into four groups. During a 14-day semi-controlled dietary study, the subjects ingested daily portions of either 150g cod, salmon, blue mussels or potato (control). Plasma concentrations of total As, FT3, FT4, TSH and selenium (Se), and urinary concentrations of iodine were monitored. Plasma concentrations of TSH increased significantly in all seafood groups. The change in plasma As, with different coefficients for each seafood group, was the dominant factor in the optimal multiple regression model for change in TSH (R2=0.47). Plasma Se and iodine were negative and positive factors, respectively. There were also indications of changes in FT4, FT3 and the FT4:FT3 ratio consistent with a net inhibiting effect of As on FT4 to FT3 conversion. Ingestion of seafood rich in various organic As species was strongly associated with an increase of the TSH concentrations in plasma. Change in TSH was positively associated with total plasma As, but varied with the type of seafood ingested. These findings indicate that organic dietary As, apparently depending on chemical form, may influence thyroid hormones and function.