Relieving the Time Squeeze? Effects of a White-Collar Workplace Change on Parents.
Employed parents perceive a time squeeze even as trends from the 1960s show they are spending more time with their children. Work conditions (e.g., hours and schedule control) would seem to affect both parents' time with children and perceived time squeeze, but most studies rely on cross-sectional data that do not establish causality. The authors examined the effects of the introduction of a workplace flexibility initiative (Results Only Work Environment [ROWE]) on changes in mothers' and fathers' perceptions of the adequacy of their time with children and actual time spent with children (N = 225). Baseline data show the importance of work conditions for parents' sense of perceived time adequacy. Panel data show that mothers (but not fathers) in ROWE report increased schedule control and improved time adequacy, but no change in actual time spent with children, except that ROWE increases evening meals with children for mothers sharing few meals at baseline.


Analysis of the effect of potato carboxypeptidase inhibitor pro-sequence on the folding of the mature protein.
Protein folding can be modulated in vivo by many factors. While chaperones act as folding catalysts and show broad substrate specificity, some pro-peptides specifically facilitate the folding of the mature protein to which they are bound. Potato carboxypeptidase inhibitor (PCI), a 39-residue protein carboxypeptidase inhibitor, is synthesized in vivo as a precursor protein that includes a 27-residue N-terminal and a seven-residue C-terminal pro-regions. In this work the disulfide-coupled folding of mature PCI in vitro has been compared with that of the same protein extended with either the N-terminal pro-sequence (ProNtPCI) or both N- and C-terminal pro-sequences (ProPCI), and also with the N-terminal pro-sequence in trans (ProNt + PCI). No significant differences can be observed in the folding kinetics or efficiencies of all these molecules. In addition, in vivo folding studies in Escherichia coli have been performed using wild-type PCI and three PCI mutant forms with and without the N-terminal pro-sequence, the mutations had been previously reported to affect folding of the PCI mature form. The extent to which the 'native-like' form was secreted to the media by each construction was not affected by the presence of the N-terminal pro-sequence. These results indicate that PCI does not depend on the N-terminal pro-sequence for its folding in both, in vitro and in vivo in E. coli. However, structural analysis by spectroscopy, hydrogen exchange and limited proteolysis by mass spectrometry, indicate the capability of such N-terminal pro-sequence to fold within the precursor form.


Phylogenetic relationship and antifouling activity of bacterial epiphytes from the marine alga Ulva lactuca.
It is widely accepted that bacterial epiphytes can inhibit the colonization of surfaces by common fouling organisms. However, little information is available regarding the diversity and properties of these antifouling bacteria. This study assessed the antifouling traits of five epiphytes of the common green alga, Ulva lactuca. All isolates were capable of preventing the settlement of invertebrate larvae and germination of algal spores. Three of the isolates also inhibited the growth of a variety of bacteria and fungi. Their phylogenetic positions were determined by 16S ribosomal subunit DNA sequencing. All isolates showed a close affiliation with the genus Pseudoalteromonas and, in particular, with the species P. tunicata. Strains of this bacterial species also display a variety of antifouling activities, suggesting that antifouling ability may be an important trait for members of this genus to be highly successful colonizers of animate surfaces and for such species to protect their host against fouling.


Enhanced-efficiency Capacitive Coupling Intra-body Power Transfer Systems with 1.8 V Output for Neural Interfaces.
Traditional wireless power transfer methods for powering neural interfaces have many restrictions such as short transmission distance and strict device alignment. The recently proposed capacitive coupling intra-body power transfer (CC-IBPT) which utilizes human body as the medium supports flexible placements of the transmitter electrode. In this paper, we established two prototype systems based on CC-IBPT with different power sources of a grounded signal generator and a battery-powered board to explore the maximum output power levels with 1.8 V load voltage. To improve the power transmission efficiency, LC impedance matching (IM) and backward compensation (BC) are conducted at the transmitter (TX) and receiver (RX) respectively. Measured results show that 2.5 and 7.4 times load power is enhanced in the two prototype systems. Moreover, the maximum power transfer efficiency (PTE) of 11.16% can be obtained with the TX-RX distance of 16 cm. Therefore, our work verifies CC-IBPT's capability of achieving a high PTE in long-distance wireless power supply for neural interfaces and promotes its widespread application.


Death notification training for prehospital providers: a pilot study.
When cardiac arrest occurs at home, family members are likely to be present during resuscitation efforts. However, little training is provided to prehospital providers on how to best manage a family-witnessed resuscitation (FWR) and deliver the news of death in the field. To study the feasibility and utility of an educational intervention designed to improve prehospital provider comfort with FWR and death notification. This was a pilot study of a convenience sample of 45 prehospital providers who participated in an educational lecture, with 20 providers then attending a small-group standardized death-notification encounter. Descriptive statistics were calculated to assess pre- and postintervention attitudes and knowledge with respect to FWR and death notification. All subjects had participated in at least one cardiac arrest resuscitation effort, with 28 (62.2%) having performed a death notification. Seventy-one percent (n = 32) of the participants have continued resuscitation efforts despite futility because the family was present. Fifty-five percent of participants (n = 25) had an interest in improving their FWR and death notification skills. After the educational seminar, 61.2% (n = 19) of all participants correctly answered at least five of the six knowledge-based questions. The small-group intervention participants showed an overall improvement in death notification skills, with a majority expressing confidence in their ability to effectively communicate with families during an unsuccessful resuscitation. This pilot study suggests that a short educational intervention can impact prehospital providers' comfort with death notification. Future research will need to be conducted on prehospital provider skill retention and the impact this training has on family members.


Gallic acid exerts protective effects in spinal cord injured rats through modulating microglial polarization.
Spinal cord injury (SCI) is a highly traumatic injury that causes mechanical damage to the spinal cord. Our study aimed to investigate whether gallic acid has protective effects against SCI injury. Adult male rats were subjected to contusive spinal cord injuries. For behavioural evaluation, the rats were given gallic acid by i.p. injection at the doses of 10, 50 or 100 mg/kg immediately after SCI once daily for consecutive 28 days. Behavioral tests were used to evaluate locomotor functions, mechanical sensitivity and nerve conduction functions. For biochemical experiments, the rats were randomly divided into three groups: sham group, SCI group and SCI+gallic acid group. The rats in the SCI+gallic acid group were given gallic acid at the dose of 100 mg/kg immediately after SCI once daily for consecutive 14 days. The levels of inflammatory factors were evaluated. Gallic acid treatment could improve locomotive and sensory function and reduce the functional impairments in SCI rats. The effects were more effective with increasing gallic acid dose. The levels of M1 markers (inducible nitric oxide synthase and cyclooxygenase-2) were decreased in gallic acid-treated SCI rats, whereas the levels of M2 markers (arginase 1 and cluster of differentiation 206) were increased in response to gallic acid administration. Gallic acid treatment resulted in a significant reduction in pro-inflammatory cytokines and an increase in anti-inflammatory cytokine levels. Gallic acid enhances the recovery in SCI rats by regulating microglial polarization. The underlying mechanism may involve the promotion of M2 polarization and the suppression of M1 polarization in microglia.


Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell.
Psychiatric disorders such as anxiety, depression and addiction are often comorbid brain pathologies thought to share common mechanistic biology. As part of the cortico-limbic circuit, the nucleus accumbens shell (NAcSh) plays a fundamental role in integrating information in the circuit, such that modulation of NAcSh circuitry alters anxiety, depression, and addiction-related behaviors. Intracellular kinase cascades in the NAcSh have proven important mediators of behavior. To investigate glycogen-synthase kinase 3 (GSK3) beta signaling in the NAcSh in vivo we knocked down GSK3beta expression with a novel adeno-associated viral vector (AAV2) and assessed changes in anxiety- and depression-like behavior and cocaine self-administration in GSK3beta knockdown rats. GSK3beta knockdown reduced anxiety-like behavior while increasing depression-like behavior and cocaine self-administration. Correlative electrophysiological recordings in acute brain slices were used to assess the effect of AAV-shGSK3beta on spontaneous firing and intrinsic excitability of tonically active interneurons (TANs), cells required for input and output signal integration in the NAcSh and for processing reward-related behaviors. Loose-patch recordings showed that TANs transduced by AAV-shGSK3beta exhibited reduction in tonic firing and increased spike half width. When assessed by whole-cell patch clamp recordings these changes were mirrored by reduction in action potential firing and accompanied by decreased hyperpolarization-induced depolarizing sag potentials, increased action potential current threshold, and decreased maximum rise time. These results suggest that silencing of GSK3beta in the NAcSh increases depression- and addiction-related behavior, possibly by decreasing intrinsic excitability of TANs. However, this study does not rule out contributions from other neuronal sub-types.


A randomized, placebo-controlled study of oral cimetidine as an immunopotentiator of parenteral immunization with a group B meningococcal vaccine.
Cimetidine (CIM) is an H2-receptor antagonist with a long history of clinical use in peptic ulcer disease. In addition to its inhibitory effect upon gastric acid secretion, CIM can also block histamine-mediated immunosuppression by inhibiting H2 receptors on suppressor T cells. CIM results in immunoaugmentation of both cellular and humoral immunity by this mechanism and has been used clinically in the treatment of chronic infectious and neoplastic diseases. We postulated that orally administered CIM, like an adjuvant, could augment the immunologic response to a parenteral vaccine. To test this hypothesis, a randomized placebo (PLB)-controlled, double-blinded study in 14 healthy volunteers was performed using a Group B meningococcal outer membrane protein (OMP) vaccine administered twice, 6 weeks apart. Volunteers were randomized within pairs defined by their screening OMP antibody titers to receive either CIM or PLB which was administered for 5 days, beginning 2 days before each of the two immunizations. All 14 volunteers completed the study with excellent compliance. Sera were tested for anti-OMP and bactericidal antibodies. The groups were comparable in terms of gender distribution, age and baseline anti-OMP titers. Reactogenicity to the vaccine was mild and comparable between groups. There was little effect of CIM (over PLB) on anti-OMP or functional bactericidal antibody levels over time. Geometric means of maximum OMP antibody increase over baseline was 3.3-fold (95% CI: 1.8-6.3) for CIM and 2.4 for PLB (CI: 1.6-3.7). CIM had a corresponding 3.9-fold increase (CI: 1.9-8.3) in bactericidal antibody level compared to 2.2 for PLB (CI: 1.4-3.4). We conclude that oral CIM was not effective as an immunopotentiator of immunization with this group B meningococcal vaccine.


Surgical treatment of deep venous insufficiency of the lower limb.
The substitute "valve" operation, using Technique II with a Silastic (polymeric silicone) tendon designed to produce a valve-like mechanism in the popliteal vein, was performed upon 162 lower limbs (145 patients) which had deep venous insufficiency. Results achieved by this procedure were assessed clinically by Doppler ultrasound and venous pressure measurements, and partially by phlebography. Clinical improvement in 154 of 162 limbs was associated with a reduction of ambulatory venous pressure, prolongation of refilling time, interruption of popliteal reflux by Doppler, and phlebographic evidence of a functioning substitute "valve" postoperatively.


Expression of functional gap junctions and regulation by fluid flow in osteocyte-like MLO-Y4 cells.
Osteocytes are thought to be mechanosensory cells that respond to mechanical stress by sending signals to other bone cells to initiate bone remodeling. An osteocyte-like cell line MLO-Y4 provides a model system to examine whether gap junctions participate in the regulation of osteocyte function and signaling by mechanical stress. In this study, we show that MLO-Y4 cells are coupled and that gap junction channels mediate this coupling. Biochemical analyses show that connexin 43 (Cx43) is a major gap junction protein expressed in MLO-Y4 cells and approximately 5% of Cx43 protein is phosphorylated. MLO-Y4 cells were exposed to mechanical stress using a parallel plate flow chamber to model bone fluid flow shear stress. Fluid flow increased significantly the length of the dendritic processes, a morphological characteristic of osteocytes. A redistribution of the gap junction protein, Cx43 also was observed from a location circling the nucleus to punctate spots in the cytoplasm and in the dendritic processes. "Scrape-loading" dye transfer analyses showed that fluid flow increased intercellular coupling and increased the number of cells coupled immediately after fluid flow treatment, in direct proportion to shear stress magnitude. Although intercellular coupling continued to increase, stimulation of Cx43 protein expression during the poststress period was found to be biphasic. Cx43 protein was elevated 30 minutes after application of stress but decreased at 24 h poststress. Pulsating fluid flow had a similar stimulatory effect as steady fluid flow on gap junctions. However, this stimulatory effect in osteocyte-like cells was not observed in osteoblast-like 2T3 cells. Together, these results show that fluid flow has stimulatory effects on osteocyte-like MLO-Y4 cells with early effects on cellular morphology, opening of gap junctions, and redistribution of Cx43 protein and delayed effects on Cx43 protein expression. The high expression of Cx43 and its location in the cytoplasm also suggest that Cx43 may have unknown functions in addition to forming gap junctions. These studies indicate that gap junctions may serve as channels for signals generated by osteocytes in response to mechanical loading.


Modeling the Metabolic State of Mycobacterium tuberculosis Upon Infection.
Genome-scale metabolic models of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, have been envisioned as a platform for drug discovery. By systematically probing the networks that underpin such models, the reactions that are essential for Mtb are identified. A majority of these reactions are catalyzed by enzymes and thus represent candidate drug targets to fight an Mtb infection. Nevertheless, this is complicated by the limited knowledge on the environment that Mtb encounters during infection. Modeling the behavior of the bacteria during infection requires knowledge of the so-called biomass reaction that represents bacterial biomass composition. This composition varies in different environments or bacterial growth phases. Accurate modeling of the metabolic state requires a precise biomass reaction for the described condition. In recent years, additional insights in the in-host environment occupied by Mtb have been gained as transcript abundance data of interacting host and pathogen have become available. Therefore, we used transcript abundance data and developed a straightforward and systematic method to obtain a condition-specific biomass reaction for Mtb during in vitro growth and during infection of its host. The method described herein is virtually free of any pre-set assumptions on uptake rates of nutrients, making it suitable for exploring environments with limited accessibility. The condition-specific biomass reaction represents the "metabolic objective" of Mtb in a given environment (in-host growth and growth on defined medium) at a specific time point, and as such allows modeling the bacterial metabolic state in these environments. Five different biomass reactions were used to predict nutrient uptake rates and gene essentiality. Predictions were subsequently compared to available experimental data. Our results show that nutrient uptake can accurately be predicted. Gene essentiality can also be predicted but accurate predictions remain difficult to obtain. In conclusion, a viable strategy to model Mtb metabolism in hard-to-access environments that is virtually free of pre-set assumptions is provided.


Dietary compliance and life style of children with coeliac disease.
Coeliac disease (CD) is common and requires a permanent strict gluten-free diet (GFD). However, data concerning how the situation is experienced by children are limited. The present study aimed to investigate the compliance with a GFD and the impact of CD and GFD on the lifestyle of patients and their families, together with proposed recommendations for improvement of quality of life. Children with biopsy confirmed CD were recruited consecutively from the outpatient gastroenterology clinic. Participants were evaluated by a special questionnaire for compliance with the GFD, patients' knowledge about CD, and the well-being and lifestyle of children and their families. Comparisons between discrete variables were performed by a chi-square test. Seventy-three children of median age 9.4 (interquartile range = 5-14.5) years were evaluated. Compliance to diet was reported by 58%. Reasons for noncompliance were: poor palatability (32%), dining outside home (17%), poor availability of products (11%), and asymptomatic disease diagnosed by screening (11%). The acceptance of the GFD was reported as good in 65%, whereas avoidance of travelling and restaurants was stated by 17% and 46% of families, respectively. Most families experienced difficulties detecting gluten from the food label. Proposed factors for improvement of quality of life were: better labelling of gluten-containing ingredients (76%) and more gluten-free (GF) foods in supermarkets (58%) and restaurants (42%). Children with CD have low compliance with the GFD. Better education about the disease, the availability of GF products, and appropriate food labelling could improve compliance and quality of life.


Predictive performance of reported vancomycin population pharmacokinetic model in patients with different renal function status, especially those with augmented renal clearance.
There is a significant correlation between augmented renal clearance (ARC) and lower serum trough concentrations of vancomycin (VCM) during therapy. There is a need to evaluate the predictive performance of the population pharmacokinetic (PPK) model used for individual calculation of dosage regimens in ARC patients. Our study aimed to estimate the predictive performance differences of the reported VCM PPK software JPKD-vancomycin and SmartDose in patients with varying renal function status, especially those with ARC. Patients receiving VCM treatment from May 2014 to December 2019 were enrolled, and divided into the ARC group, the normal renal function (NRF) group, and the impaired renal function (IRF) group. VCM dosage, trough concentration, area under the curve (AUC) and pharmacokinetic parameters were compared among the three groups. The predictive performance of PPK software was expressed using absolute prediction error (APE), sensitivity, specificity, and regression coefficient (r2) of linear regression analysis between the measured VCM trough concentration and the predicted trough concentration. A total of 388 patients were included: 86 patients in the ARC group, 241 patients in the NRF group, and 61 patients in the IRF group. The daily dose of the adjusted regimen in the ARC group was higher than in the NRF group, but the trough concentration was significantly lower than in the NRF group (2.8±0.6 g vs 1.9±0.6 g, p<0.001; 10.5±5.1 mg/L vs 12.9±6.8 mg/L, p=0.030). The percentage of trough concentrations lower than 10 mg/L was 84.9% in the ARC group. Compared with the APE of the initial dosage regimen, the APE of the adjusted regimen calculated by JPKD was lower in the ARC group (p=0.041) and the NRF group (p<0.001). Specificity of JPKD and SmartDose in the ARC group was higher than in the NRF group (p<0.001; p<0.001). According to the linear regression analysis, the coefficients of determination (r2) were all >0.6 for the initial regimen and adjusted regimen of VCM in the ARC and NRF groups, and the r2 of the adjusted regimen of JPKD was >0.8 in the ARC and NRF groups. In the IRF group, 31.1% of patients had a change in serum creatinine (Scr) level of >50%. The r2 increased from 0.527 to 0.7347 in SmartDose and from 0.55 to 0.7802 in JPKD when using Scr at the sampling time. The ARC group showed a significant decrease in AUC (p<0.001) and an increase in clearance rate (p<0.001) when compared to the NRF group. ARC was significantly associated with subtherapeutic serum VCM concentration. The pharmacokinetic parameters of VCM were diverse in patients with different renal function status. The PPK model JPKD and SmartDose had a good predictive performance for predicting VCM trough concentrations of the ARC and NRF patients, especially using JPKD for prediction of the adjusted regimen. The change of Scr is a main factor affecting the accuracy of software prediction.


Rheumatic manifestations preceding adult acute leukemia: characteristics and implication in course and prognosis.
The manifestations and outcome of adult patients with acute leukemia (AL) were examined to study the characteristics of the rheumatological prodrome of AL and to find whether it is a marker of a distinct clinical and laboratory course and whether it has any prognostic implication. During a 10-year period, 8/139 (5.8%) of AL patients presented with rheumatic manifestations. The average duration of the arthritis syndrome preceding the diagnosis of AL was 3.25 months. The most common pattern of presentation was a reactive arthritis-like syndrome involving the large joints asymmetrically and associated with low back pain. Distinctive features suggesting a paraneoplastic arthritis were severe pain disproportionate to physical findings, a poor response to conventional antirheumatic treatment, and early significant osteopenia or lytic bone lesions. The epidemiological, clinical and laboratory characteristics of patients with or without rheumatic manifestations were comparable, except for fever on presentation, the presence of transient metabolic derangement following chemotherapy, and the initial average hemoglobin, hematocrit and serum uric acid values. Moreover, the initial outcome of the two groups was similar, as the early mortality rates were comparable (42.8% vs. 45% for patients with or without arthritis, respectively). In conclusion, rheumatic syndrome presentation of adult AL is uncommon, and apparently has no deleterious effects on initial prognosis. A timely diagnosis requires an increased awareness to distinctive features.


Constellations of dyadic relationship quality in stepfamilies: A factor mixture model.
Stepfamilies are an increasingly common family form, marked by distinct challenges, opportunities, and complex networks of dyadic relationships that can transcend single households. There exists a dearth of typological analyses by which constellations of dyadic processes in stepfamilies are holistically analyzed. Factor mixture modeling is used to identify population heterogeneity with respect to features of mother-child, stepfather-child, nonresident father-child, and stepcouple relationships using a representative sample of 1,182 adolescents in mother-stepfather families with living nonresident fathers from Wave I of the National Longitudinal Study of Adolescent to Adult Health. Results favor a 4-class factor-mixture solution with class-specific factor covariance matrices. Class 1 (n = 302, 25.5%), the residence-centered pattern, was marked by high-quality residential relationships. Class 2 (n = 307, 26%), the inclusive pattern, was marked by high-quality relationships across all four dyads, with an especially involved nonresident father-child relationship. Class 3 (n = 350, 29.6%), the unhappy couple pattern, was marked by very low stepcouple relationship quality. Class 4 (n = 223, 18.9%), the parent-child disconnection pattern, was marked by distant relationships between youth and all three parental figures. The residence-centered and inclusive patterns encompassed some positive correlations between dyadic relationships whereas the unhappy couple and parent-child disconnection patterns encompassed some negative correlations between dyadic relationships. The patterns present with differences across sociodemographic and substantive covariates and highlight important opportunities for the development of new and innovative interventions, particularly to meet the needs of stepfamilies that reflect the parent-child disconnection pattern. (PsycINFO Database Record


Pressure-Tuned Fermi Resonance in Ice VII.
Fermi resonance was observed between the OH stretch and the overtone of the OH bending modes of HDO molecules contaminated in phase VII of D(2)O ice over the pressure range from 17 to 30 gigapascals. An anharmonic coupling constant, which is related to the potential energy surface on which hydrogen-bonded protons oscillate, was found to range around 50 wave numbers through the resonant pressure range. Its experimentally obtained magnitude and pressure-insensitive behavior will be useful for theoretical studies of the potential energy surface and hence of the nature of hydrogen bonding in ice.


Triphasic changes in thyroid function in a patient with primary hypothyroidism in the course of pregnancy and the early post-partum period.
We report a rare case of primary hypothyroidism in which thyroid function was changed from hypothyroidism to hyperthyroidism in the course of pregnancy and finally returned to hypothyroidism in the early post-partum period. She delivered an infant with neonatal Graves' thyrotoxicosis. Serum thyroid-stimulating antibodies (TSAb) and thyroid stimulating-blocking antibodies (TSBAb) coexisted in these patients. The triphasic changes in thyroid function may be explained by altered balance between TSAb and TSBAb in relation to pregnancy and delivery in the present case, although cellular immunity could be independently involved in atrophic changes in the postpartum period.


Sex differences in the plasticity of life history in response to social environment.
Predicting how social environment affects life history variation is critical to understanding if, and when, selection favors alternative life history development, especially in systems in which social interactions change over time or space. Although sexual selection theory predicts that males and females should respond differently to variation in the social environment, few studies have examined the responses of both male and female phenotypes to the same gradient of social environment. In this study, we used a livebearing fish to determine how males and females altered their life histories in response to variation in the social environment during development. We found that both males and females delayed maturity and attained larger sizes when their social environment included adults, in contrast to developing in juvenile-only environments. The magnitude of this effect differed substantially between the sexes. The common pattern of response in the sexes suggested that life history trade-offs, rather than sexual selection, is responsible for these changes in life history expression. These effects make the relationship between genotype and phenotype depend strongly on the environment experienced by each individual. These results indicate that social environment is an important driver of life history variation in sailfin mollies and can be at least as important as abiotic effects.


Antagonists of growth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice.
Antagonists of growth hormone-releasing hormone(GH-RH)inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF)-I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1 -36 at the dose of 20 microg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01) decreased by 84% and 76%, respectively, as compared with controls. Treatment with GH-RH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I). A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1 -36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005) and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1 -36 at 1 microM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U-87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-1-36 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma.


Cell cycle-dependent transduction of cell-permeant Cre recombinase proteins.
Protein transduction has been widely used to analyze biochemical processes in living cells quantitatively and under non-steady-state conditions. The present study analyzed the effects of cell cycle on the uptake and activity of cell-permeant Cre recombinase proteins. Previous studies had suggested that the efficiency of recombination and/or protein transduction varied among individual cells, even within a clonal population. We report here that cells in the G1 phase of the cell cycle undergo recombination at a lower rate than cells at other phases of the cell cycle, and that this variation results largely from differences in protein uptake, associated with differences in cell size. These results have implications regarding the mechanism of protein transduction and identify a source of heterogeneity that can influence the response of individual cells to cell-permeant proteins.


[Immediate and long-term results of surgery of the tricuspid valve. APropos of 62 operated cases].
Operative and late results in a series of patients operated on the tricuspid valve (replacement or annuloplasty) at the moment of surgery upon mitral and aortic valves are reported. Functional tricuspid insufficiency carries a greater risk than organic tricuspid disease. Considering the duration of the underlying mitral disease, four grades are set up for the mitro-tricuspid patient allowing for prognosis and indication of the type of surgery to be done on the tricuspid valve.


Inhibitory effect of hyperosmolality on catecholamine secretion from the bovine adrenal medulla.
We examined the effect of hyperosmolality on exocytotic catecholamine secretion in isolated-perfused bovine adrenals, in both the absence and presence of Ca2+ in the extracellular medium. Exposure of adrenal glands to hyperosmotic media (600 mOsm/Kg H2O) for 20 minutes significantly decreased spontaneous catecholamine output, and was independent of extracellular Ca2+ concentration. Adrenal glands were exposed to a hyperosmotic Locke solution (600 mOsm/Kg H2O) for 10 minutes and then stimulated with acetylcholine. Hyperosmolality produced a significant, reversible inhibition of acetylcholine-evoked catecholamine secretion. As the osmotic strength of the perfusion fluid was increased, either by addition of sucrose or NaCl, there was a progressive reduction in the acetylcholine response. Hyperosmolality also decreased catecholamine release induced by 56 mM K+ and by removal of NaCl from the perfusion medium. Similar results were seen in glands exposed to a NaCl-free solution in the absence of extracellular Ca2+. These results suggest that inhibitory effects of hyperosmolality on stimulus-secretion coupling in the adrenal medulla are exerted after Ca2+ enters the chromaffin cells, and support one of the primary criteria of the chemiosmotic hypothesis.


Mandibular Reconstruction Using Free Fibular Flap Graft Following Excision of Calcifying Epithelial Odontogenic Tumor.
The calcifying epithelial odontogenic tumor (CEOT) is a rare benign odontogenic tumor, which usually presents with distension of affected tissues. Radiologically, the lesions are often associated with an unerupted tooth and may have spot calcification shadows. The authors report a case of a CEOT in a 48-year-old male involving the right mandibular jaw bone and mentum soft tissues. The authors performed hemimandibulectomy and enucleation followed by reconstruction of the mandible using a vascularized free fibular flap through a digital surgical technique in order to restore the patient's facial symmetry and prepare the area for functional restorations. The case illustrates who the free fibular flap graft can be used for satisfactory mandibular reconstruction and restoration of the morphology and functions.


Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells.
Cell migration followed by matrix invasion is a critical step required for epithelial cell differentiation, growth and survival. This study determined the RON receptor in regulation of motile-invasive phenotypes of epithelial cells. Two RON variants, RON165.e11p and RON165, with alterations in a defined extracellular domain were used as the model. RON165 is a splicing variant generated by an mRNA transcript with an in-frame deletion of 49 amino acids encoded by exon 11. In contrast, RON165.e11p was produced by a partial deletion of exon 11 with the elimination of the first 40 amino acids. Thus, RON165.e11p differs from RON165 with nine amino acids retained in the fourth immunoglobulin-plexin-transcription (IPT) domain. Biochemically, both RON165 and RON165.e11p exist as a single-chain protein, residing in the cytoplasm, and failed to mature into the two-chain receptor. Both RON165 and RON165.e11p spontaneously formed oligomers in vivo leading to constitutive phosphorylation and the activation of downstream signaling proteins. Although lacking cell-transforming activities, RON165 and RON165.e11p mediated the epithelial to mesenchymal transition with spindle-like cell morphologies, diminished E-cadherin expression, and increased N-cadherin and vimentin expression. These changes facilitated epithelial cell migration and invasion as modeled in Martin-Darby canine kidney (MDCK) cells. Moreover, expression of RON165 or RON165.e11p in breast epithelial MCF-7 cells diminished epithelial cell phenotypes and increased motile and invasive activities. Thus, alterations in the defined extracellular region result in two unique RON variants with similar biological properties. The ability of RON165 or RON165.e11p to promote motile-invasive phenotypes may represent a mechanism by which RON regulates epithelial cell phenotypes and biological activities.


Geminal bis-borane formation by borane Lewis acid induced cyclopropyl rearrangement and its frustrated Lewis pair reaction with carbon dioxide.
Cyclopropylacetylene reacts with two molar equivalents of Piers' borane [HB(C6F5)2] under mild conditions by an addition/rearrangement sequence with cyclopropyl ring opening to give a mixture of two α-B(C6F5)2 substituted tetrahydroboroles. This compound forms an active frustrated Lewis pair with P t Bu3 that heterolytically splits dihydrogen and adds carbon dioxide as a geminal chelate bis-boryl component. The respective reactions of the two-fold HB(C6F5)2 addition to Ph-CH2CH2C[triple bond, length as m-dash]CH were studied as a geminal Lewis acid reference. Most of the products were characterized by X-ray diffraction.


Cerebrospinal fluid leak associated with nasal continuous positive airway pressure treatment for obstructive sleep apnoea.
Clear rhinorrhoea is a common symptom in patients with obstructive sleep apnoea (OSA), which may worsen with nasal continuous positive airway pressure treatment (nCPAP). However, rhinorrhoea can also be the presenting symptom of cerebrospinal fluid (CSF) leak, which is due to a communication between the subarachnoid space and the nasal cavity or sinuses. We report another case of a patient with OSA in whom CSF leak developed following the initiation of nCPAP treatment.


MEMS-Based Tactile Sensors: Materials, Processes and Applications in Robotics.
Commonly encountered problems in the manipulation of objects with robotic hands are the contact force control and the setting of approaching motion. Microelectromechanical systems (MEMS) sensors on robots offer several solutions to these problems along with new capabilities. In this review, we analyze tactile, force and/or pressure sensors produced by MEMS technologies including off-the-shelf products such as MEMS barometric sensors. Alone or in conjunction with other sensors, MEMS platforms are considered very promising for robots to detect the contact forces, slippage and the distance to the objects for effective dexterous manipulation. We briefly reviewed several sensing mechanisms and principles, such as capacitive, resistive, piezoresistive and triboelectric, combined with new flexible materials technologies including polymers processing and MEMS-embedded textiles for flexible and snake robots. We demonstrated that without taking up extra space and at the same time remaining lightweight, several MEMS sensors can be integrated into robotic hands to simulate human fingers, gripping, hardness and stiffness sensations. MEMS have high potential of enabling new generation microactuators, microsensors, micro miniature motion-systems (e.g., microrobots) that will be indispensable for health, security, safety and environmental protection.


Tumor cell dormancy as an adaptive cell stress response mechanism.
Metastases are responsible for most cancer-related deaths. The kinetics of tumor relapse is highly heterogeneous, ranging from recurrences shortly after diagnosis to years or even decades after the initial treatment. This subclinical period is known as tumor dormancy, in which residual disease remains in an undetectable state before finally appearing as an overtly proliferative metastasis. Despite recent advances in our understanding of the molecular mechanisms leading to tumor dormancy, it is still a poorly understood phase of cancer progression, which limits opportunities for the design of successful therapeutic interventions. The influence of the tumor microenvironment at the metastatic site and anti-metastatic immune responses have been shown to play a crucial role in the onset and maintenance of metastatic dormancy. However, there is still a significant gap in our understanding of how dormant cells remain viable in a quiescent state for long periods of time. Here, we review the latest experimental evidence shedding light on the biological processes that enable dormant tumor cells to endure the multiple stresses encountered at the metastatic site.


Vasoactive intestinal peptide induces vascular endothelial growth factor production in human HaCaT keratinocytes via MAPK pathway.
Psoriasis is a chronic skin disease characterized by abnormal keratinocyte proliferation and differentiation, inflammation, and angiogenesis. Although dysfunction of the immune system is known to be an important factor in the pathogenesis of psoriasis, there is also strong evidence that psychological stresses are involved. Neuropeptides are thought to be main mediators of neurogenic inflammation, presumably involved in the pathogenesis of psoriasis. Vasoactive intestinal peptide (VIP) is one of the major neuropeptides in human and rodent skin. In the present study, we examined the effect and mechanism of VIP on vascular endothelial growth factor (VEGF) production by HaCaT cells which is a spontaneous, immortalized, human keratinocyte cell line. Our data indicate the mRNA and protein levels of VEGF by VIP were increased in a concentration-dependent manner. However, this increase was abrogated by pretreatment with an extracellular signal-regulated kinase (ERK) inhibitor PD98059 or p38MAPK inhibitor SB203580; pretreatment with c-Jun N-terminal kinase (JNK) inhibitor SP600125 did not attenuate the effects of VIP on the expression of VEGF. In addition, VIP treatment induced rapid phosphorylation of ERK1/2 and p38MAPK, and PD98059 and SB203580 were able to inhibit VIP-induced phosphorylation of ERK1/2 and p38MAPK, respectively. These results suggest that VIP increases the expression of VEGF through the ERK1/2 and p38MAPK signaling pathway in human HaCaT cells.


Perturbation of the antigen-binding site and staphylococcal protein A-binding site of IgG before significant changes in global conformation during denaturation: an equilibrium study.
Although conformational perturbation of the active sites of many enzymes has been reported to precede global molecular conformational changes [Tsou (1993) Science 262, 380-381], little effort has been made to compare the susceptibility of the ligand-binding site of proteins and the protein molecules as a whole to perturbation by denaturants. Immunoglobulin is chosen in this study to address this problem. It is found that the variable and constant regions (Fv and Fc) of a monoclonal antibody of an IgG subclass against adenylate kinase lose their abilities to bind antigen and staphylococcal Protein A after treatment with guanidinium chloride concentrations considerably lower than those required to change the global conformation of the antibody as a whole, as detected by fluorescence and second-derivative UV absorption spectroscopy. These results indicate that both ligand-binding sites of the antibody concerned are more fragile than the molecule as a whole and that the Fv and Fc regions of the antibody molecule unfold sequentially during denaturation.


Short-term effects of a chicken egg shell powder enriched dairy-based products on bone mineral density in persons with osteoporosis or osteopenia.
Based on the high calcium content, chicken egg shells are an interesting source of calcium. We studied the short-term effects on bone mineral density (BMD) of the lumbar spine and hip in 9 women and one man (mean age +/- SD, 63.9 +/- 8.1 years) with osteoporosis or osteopenia. Also the effects on pain and general well-being were monitored. Ten women (62.5 +/- 5.0 years) from a population study on BMD served as a control group. During a study period of 4-8 months, the intervention group consumed twice daily a dairy-based supplement which resulted in a daily intake of, among others, 3.0 g of egg shell powder, 400 IU of vitamin D3 and 400 mg of magnesium. BMD of the lumbar spine (anteroposterior (AP) and lateral (LA) position) and hip were measured by dual-energy X-ray absorptiometry. After the intervention period, BMDs of the lumbar spine, total proximal femur and trochanter were significantly (p < 0.05) increased with (median) 4.4%: (range) 1.7 to 10.4% (lumbar spine AP), 5.7%: -1.3 to 15.9% (lumbar spine LA), 2.2%: -1.9 to 9.4% (total proximal femur), 1.8%: -1.8 to 9.0% (trochanter). Within a period of 4 months, an important reduction in pain was reported and as a consequence an improvement in general well-being. In the control group, BMDs of the lumbar spine AP and of the femoral neck significantly decreased over a period of 8 months with -0.7% (-1.3 to 0.2%) and -0.9% (-2.4 to -0.1%) respectively. Six women of the intervention group continued to use the supplement on their own free will and without any check on compliance, up to 24 months. They consumed the supplement only once daily except for the last three months when they were asked to take the double dosage again. After 24 months BMDs did not differ from baseline. This study shows that egg shell powder is a source of bioavailable calcium. Furthermore, this pilot study indicates that the chicken egg shell powder enriched dairy-based supplement increases BMD of subjects with a low bone mass in the short term and as a consequence delays bone demineralisation for a longer period. (Tab. 3, Fig. 1, Ref. 23.)


Mandibular rotation and remodeling changes during early childhood.
To describe the mandibular rotation and remodeling of younger children. The sample included 43 males and 43 females who participated in the Bolton-Brush Growth Study at Case Western Reserve University in Ohio. They were chosen on the basis of having Class I (n = 45) or Class II (n = 41) molar relationships and longitudinal lateral cephalograms at three developmental stages of the dentition: late primary (T1: 5.7 +/- 0.5 y), early mixed (T2: 8.4 +/- 0.6 y), and full permanent dentition (T3: 15.4 +/- 0.5 y). Each subject's cephalograms were traced and four landmarks were digitized. Cranial base and mandibular superimpositions were performed with the use of natural reference structures. Yearly rates of true rotation, apparent rotation, and angular remodeling showed significant (P < .05) changes throughout. True rotation was moderately correlated with angular remodeling and apparent rotation. Although no significant sex differences in annual rates of rotation were noted, subjects with Class I molar relationships showed significantly more angular remodeling from T2-T3 than did subjects with Class II molar relationships. Rates of true forward rotation were significantly greater with T1-T2 than with T2-T3 (1.3 and 0.7 degrees/y, respectively). Although significant amounts of true mandibular rotation and angular remodeling occur during childhood and adolescence, true rotation is greatest during the transition from late primary to early mixed dentition.


Hyperpigmented melanistic skin lesions of smallmouth bass Micropterus dolomieu from the Chesapeake Bay watershed.
Hyperpigmented melanistic skin lesions (HPMLs) of smallmouth bass Micropterus dolomieu are observed in the Potomac and Susquehanna rivers, Chesapeake Bay watershed, USA. Routine, nonlethal population surveys were conducted at 8 sites on the mainstem Susquehanna River and 9 on the Juniata River, a tributary of the Susquehanna River, between 2012 and 2018, and the prevalence of HPMLs was documented. A total of 4078 smallmouth bass were collected from the mainstem Susquehanna River and 6478 from the Juniata River. Lesions were primarily seen in bass greater than 200 mm, and prevalence in the Susquehanna River (8%) was higher (p < 0.001) than in the Juniata River (2%). As part of ongoing fish health monitoring projects, smallmouth bass were collected at additional sites, primarily tributaries of the Susquehanna (n = 758) and Potomac (n = 545) rivers between 2013 and 2018. Prevalence in the Susquehanna River (13%) was higher (p < 0.001) than the Potomac (3%). Microscopically, HPMLs were characterized by an increased number of melanocytes in the epidermis or within the dermis and epidermis. RNAseq analyses of normal and melanistic skin identified 3 unique sequences in HPMLs. Two were unidentified and the third was a viral helicase (E1). Transcript abundance in 16 normal skin samples and 16 HPMLs showed upregulation of genes associated with melanogenesis and cell proliferation in HPMLs. The E1 transcript was detected in 12 of the 16 melanistic areas but in no samples from normal skin. Further research will be necessary to identify the putative new virus and determine its role in melanocyte proliferation.


Transcranial direct current stimulation of the occipital lobes with adjunct lithium attenuates the progression of cognitive impairment in patients with first episode schizophrenia.
There is no standard effective treatment for schizophrenia-associated cognitive impairment. Efforts to use non-invasive brain stimulation for this purpose have been focused mostly on the frontal cortex, with little attention being given to the occipital lobe. We compared the effects of nine intervention strategies on cognitive performance in psychometric measures and brain connectivity measured obtained from functional magnetic resonance imaging analyses. The strategies consisted of transcranial direct current stimulation (t-DCS) or repetitive transcranial magnetic stimulation (r-TMS) of the frontal lobe or of the occipital alone or with adjunct lithium, or lithium monotherapy. We measured global functional connectivity density (gFCD) voxel-wise. Although all nine patient groups showed significant improvements in global disability scores (GDSs) following the intervention period (vs. before), the greatest improvement in GDS was observed for the group that received occipital lobe-targeted t-DCS with adjunct lithium therapy. tDCS of the occipital lobe improved gFCD throughout the brain, including in the frontal lobes, whereas stimulation of the frontal lobes had less far-reaching benefits on gFCD in the brain. Adverse secondary effects (ASEs) such as heading, dizziness, and nausea, were commonly experienced by patients treated with t-DCS and r-TMS, with or without lithium, whereas ASEs were rare with lithium alone. The most effective treatment strategy for impacting cognitive impairment and brain communication was t-DCS stimulation of the occipital lobe with adjunct lithium therapy, though patients often experienced headache with dizziness and nausea after treatment sessions.


Combination therapy of Tocilizumab and steroid for management of COVID-19 associated cytokine release syndrome: A single center experience from Pune, Western India.
Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednislone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroid in COVID-19 associated CRS.This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India between April 2 and November 2, 2020. All patients administered TCZ and steroids during this period were included. The primary endpoint was incidence of all cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of systemic and infectious complications. Baseline and time dependent risk factors significantly associated with death were identified by Relative risk estimation.Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. Thirty seven percent patients were managed in wards and did not need intensive care unit (ICU) admission. Infectious complications like hospital acquired pneumonia, blood stream bacterial and fungal infections were observed in 2.13%, 2.13% and 0.06% patients respectively. Age ≥ 60 years (P = .014), presence of co-morbidities like hypertension (P = .011), IL-6 ≥ 100 pg/ml (P = .002), D-dimer ≥ 1000 ng/ml (P < .0001), CT severity index ≥ 18 (P < .0001) and systemic complications like lung fibrosis (P = .019), cardiac arrhythmia (P < .0001), hypotension (P < .0001) and encephalopathy (P < .0001) were associated with increased risk of death.Combination therapy of TCZ and steroids is likely to be safe and effective in management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled trials.


Maker Buoy Variants for Water Level Monitoring and Tracking Drifting Objects in Remote Areas of Greenland.
Meltwater runoff from the Greenland Ice Sheet changes water levels in glacial lakes and can lead to glacial lake outburst flooding (GLOF) events that threaten lives and property. Icebergs produced at Greenland's marine terminating glaciers drift into Baffin Bay and the North Atlantic, where they can threaten shipping and offshore installations. Thus, monitoring glacial lake water levels and the drift of icebergs can enhance safety and aid in the scientific studies of glacial hydrology and iceberg-ocean interactions. The Maker Buoy was originally designed as a low-cost and open source sensor to monitor surface ocean currents. The open source framework, low-cost components, rugged construction and affordable satellite data transmission capabilities make it easy to customize for environmental monitoring in remote areas and under harsh conditions. Here, we present two such Maker Buoy variants that were developed to monitor water level in an ice-infested glacial lake in southern Greenland and to track drifting icebergs and moorings in the Vaigat Strait (Northwest Greenland). We describe the construction of each design variant, methods to access data in the field without an internet connection, and deployments in Greenland in summer 2019. The successful deployments of each Maker Buoy variant suggest that they may also be useful in operational iceberg management strategies and in GLOF monitoring programs.


[Disorder of adrenal gland function in chronic fatigue syndrome].
Chronic fatigue syndrome (CFS) is defined as constellation of the prolonged fatigue and several somatic symptoms, in the absence of organic or severe psychiatric disease. However, this is an operational definition and conclusive biomedical explanation remains elusive. Similarities between the signs and symptoms of CFS and adrenal insufficiency prompted the research of the hypothalamo-pituitary-adrenal axis (HPA) derangement in the pathogenesis of the CFS. Early studies showed mild glucocorticoid deficiency, probably of central origin that was compensated by enhanced adrenal sensitivity to ACTH. Further studies showed reduced ACTH response to vasopressin infusion. The response to CRH was either blunted or unchanged. Cortisol response to insulin induced hypoglycaemia was same as in the control subjects while ACTH response was reported to be same or enhanced. However, results of direct stimulation of the adrenal cortex using ACTH were conflicting. Cortisol and DHEA responses were found to be the same or reduced compared to control subjects. Scott et al found that maximal cortisol increment from baseline is significantly lower in CFS subjects. The same group also found small adrenal glands in some CFS subjects. These varied and inconsistent results could be explained by the heterogeneous study population due to multifactorial causes of the disease and by methodological differences. The aim of our study was to assess cortisol response to low dose (1 microgram) ACTH using previously validated methodology. We compared cortisol response in the CFS subjects with the response in control and in subjects with suppressed HPA axis due to prolonged corticosteroid use. Cortisol responses were analysed in three subject groups: control (C), secondary adrenal insufficiency (AI), and in CFS. The C group consisted of 39 subjects, AI group of 22, and CFS group of nine subjects. Subject data are presented in table 1. Low dose ACTH test was started at 0800 h with the i.v. injection of 1 microgram ACTH (Galenika, Belgrade, Serbia). Blood samples for cortisol determination were taken from the i.v. cannula at 0, 15, 30, and 60 min. Data are presented as mean +/- standard error (SE). Statistical analysis was done using ANOVA with the Games-Howell post-hoc test to determine group differences. ACTH dose per kg or per square meter of body surface was not different between the groups. Baseline cortisol was not different between the groups. However, cortisol concentrations after 15 and 30 minutes were significantly higher in the C group than in the AI group. Cortisol concentration in the CFS group was not significantly different from any other group (Graph 1). Cortisol increment at 15 and 30 minutes from basal value was significantly higher in C group than in other two groups. However, there was no significant difference in cortisol increment between the AI and CFS groups at any time of the test. On the contrary, maximal cortisol increment was not different between CFS and other two groups, although it was significantly higher in C group than in the AI group. Maximal cortisol response to the ACTH stimulation and area under the cortisol response curve was significantly larger in C group compared to AI group, but there was no difference between CFS and other two groups. Several previous studies assessed cortisol response to ACTH stimulation. Hudson and Cleare analysed cortisol response to 1 microgram ACTH in CFS and control subjects. They compared maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve. There was no difference between the groups in any of the analysed parameters. However, authors commented that responses were generally low. On the contrary Scott et al found that cortisol increment at 30 min is significantly lower in the CFS than in the control group. Taking into account our data it seems that the differences found in previous studies papers are caused by the methodological differences. We have shown that cortisol increment at 15 and 30 min is significantly lower in CFS group than in C group. Nevertheless, maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve were not different between the C and CFS groups. This is in agreement with our previous findings that cortisol increment at 15 minutes has the best diagnostic value of all parameters obtained during of low dose ACTH test. However, there was no difference between CFS and AI group in any of the parameters, although AI group had significantly lower cortisol concentrations at 15 and 30 minutes, maximal cortisol response, area under the cortisol curve, maximal cortisol increment, and maximal cortisol change velocity than C group. Consequently, reduced adrenal responsiveness to ACTH exists in CFS. In conclusion, we find that regarding the adrenal response to ACTH stimulation CFS subjects present heterogeneous group. In some subjects cortisol response is preserved, while in the others it is similar to one found in secondary adrenal insufficiency.


Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.


Ethnomedicinal plants in Champadevi rural municipality, Okhaldhunga district, Nepal.
Okhaldhunga is a hilly district with fragile socioeconomic conditions, limited access to health care, social stigma, and poor resource management, where most people rely on medicinal plants for primary health care. The use of medicinal plants for primary health care varies with socioeconomic attributes. Following the intra-cultural analysis, we documented and tested the hypothesis that use of medicinal plants in Champadevi, Okhaldhunga, Nepal, depends on socioeconomic variables. We interviewed 224 respondents, 53.12% female and 46.88% male, including 31 Brahmin, 157 Chhetri, 13 Dalit, and 23 Janajati, and conducted three focused group discussions and seven key informant interviews to record the ethnomedicinal plants used in Champadevi rural municipality, Okhaldhunga District. The relative frequency of citation (RFC) was computed to know the importance of the species. A generalized linear model (GLM) was used to see the relationship between medicinal plants reported with the sociocultural variables, which include age, gender, occupation, education, ethnicity, and religion. We documented 149 medicinal plants, including 69 herbs, 22 shrubs, nine climbers, 48 trees, and one parasitic plant, belonging to 68 families and 130 genera, and used to treat 48 distinct diseases and ailments. Plant parts, leaf, and digestive disorders were frequently treated during healing. Curcuma angustifolia was the most cited species with RFC 0.9554. The respondents' knowledge of medicinal plant use varied significantly with age (p = 0.0001) and occupation (p = 0.003). Changes in land use, population decline of medicinal plant species, and unsustainable harvesting practices constituted the local threats to medicinal plants and associated knowledge. Elders died without passing on their knowledge to the younger generations during sociocultural transformation, and youth disinterest coupled with the free availability of allopathic medicine led to knowledge erosion. The use of medicinal plants in Champadevi, Okhaldhunga, was significantly depended on two socioeconomic variables age and occupation. Ethnomedicinal plants are essential in the primary healthcare system in Nepal; however, their availability and practices are declining. Thus, plans regulating land use change and human migration, acknowledging traditional healthcare practices, and raising awareness of the significance of traditional medical practices as complementary healthcare practices should be strengthened.


Achatina fulica (Mollusca: Achatinidae) Naturally Infected with Caenorhabditis briggsae (Dougherty and Nigon, 1949) (Nematoda: Rhabditidae).
Specimens of the African snail Achatina fulica, collected in Bucaramanga, Colombia, were examined for parasites. Numerous specimens of Caenorhabditis briggsae were collected from the digestive tract of the snails and identified by the structure of male spiculum, caudal bursa, gubernaculum and precloacal lip in males, triangular tooth in metarhabdion, and protandrous hermaphrodites with a female:male ratio of 15:1 and with morphometry. DNA sequences of the ITS2 region of the ribosomal gene array from worms in this study matched with 99% similarity to published sequences of C. briggsae. A redescription of the species is provided. This is the first record of the species in South America.


Aneurysm rebleeding before therapy: a predictable disaster?
OBJECTIVECurrent guidelines for subarachnoid hemorrhage (SAH) include early aneurysm treatment within 72 hours after ictus. However, aneurysm rebleeding remains a crucial complication of SAH. The aim of this study was to identify independent predictors allowing early stratification of SAH patients for rebleeding risk.METHODSAll patients admitted to the authors' institution with ruptured aneurysms during a 14-year period were eligible for this retrospective study. Demographic and radiographic parameters, aneurysm characteristics, medical history, and medications as well as baseline parameters at admission (blood pressure and laboratory parameters) were evaluated in univariate and multivariate analyses. A novel risk score was created using independent risk factors.RESULTSData from 984 cases could be included into the final analysis. Aneurysm rebleeding occurred in 58 cases (5.9%), and in 48 of these cases (82.8%) rerupture occurred within 24 hours after SAH. Of over 30 tested associations, preexisting arterial hypertension (p = 0.02; adjusted odds ratio [aOR] 2.56, 1 score point), aneurysm location at the basilar artery (p = 0.001, aOR 4.5, 2 score points), sac size ≥ 9 mm (p = 0.04, aOR 1.9, 1 score point), presence of intracerebral hemorrhage (p = 0.001, aOR 4.29, 2 score points), and acute hydrocephalus (p < 0.001, aOR 6.27, 3 score points) independently predicted aneurysm rebleeding. A score built upon these parameters (0-9 points) showed a good diagnostic accuracy (p < 0.001, area under the curve 0.780) for rebleeding prediction.CONCLUSIONSCertain patient-, aneurysm-, and SAH-specific parameters can reliably predict aneurysm rerupture. A score developed according to these parameters might help to identify individuals that would profit from immediate aneurysm occlusion.


Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes.
Extracellular vesicles (EVs) are nanoscale membrane-derived vesicles that serve as intercellular messengers carrying lipids, proteins, and genetic material. Substantial evidence has shown that cancer-derived EVs, secreted by tumor cells into the blood and other bodily fluids, play a critical role in modulating the tumor microenvironment and affecting the pathogenesis of cancer. Here we demonstrate for the first time that squamous cell carcinoma (SCC) EVs were enriched with the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in malignancies. Overexpression of Dsg2 increased EV release and mitogenic content including epidermal growth factor receptor and c-Src. Inhibiting ectodomain shedding of Dsg2 with the matrix metalloproteinase inhibitor GM6001 resulted in accumulation of full-length Dsg2 in EVs and reduced EV release. When cocultured with Dsg2/green fluorescence protein-expressing SCC cells, green fluorescence protein signal was detected by fluorescence-activated cell sorting analysis in the CD90+ fibroblasts. Furthermore, SCC EVs activated Erk1/2 and Akt signaling and enhanced fibroblast cell proliferation. In vivo, Dsg2 was highly up-regulated in the head and neck SCCs, and EVs isolated from sera of patients with SCC were enriched in Dsg2 C-terminal fragment and epidermal growth factor receptor. This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.-Overmiller, A. M., Pierluissi, J. A., Wermuth, P. J., Sauma, S., Martinez-Outschoorn, U., Tuluc, M., Luginbuhl, A., Curry, J., Harshyne, L. A., Wahl, J. K. III, South, A. P., Mahoney, M. G. Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes.


[Speech disorders in ENT practice].
The most frequent speech and language disorders which ENT doctors are confronted with are generally known to be and presented as: delayed speech and language development, dystalia, dysglossia, rhinolalia, dysarthria, and verbal fluency disorders (stuttering, cluttering). The diagnostic portion in comparison to the therapeutic part is always greater and quite different. The close cooperation with representatives of phoniatrics and pedaudiology, as well as logopedics and other specialities such as neurology, and internal medicine is highly necessary.


Social interaction in nonhuman primates: an underlying theme for primate research.
Social living is assumed to be a critical feature of nonhuman primate existence inasmuch as most primate species live in social groups in nature. Recent USDA legislation emphasizes the importance of social contact in promoting psychological well-being and recommends that laboratory primates be housed with companions when consistent with research protocols. Our goals were to examine the link between social housing and psychological well-being and to explore the idea that research may be compromised when primates are studied in environments that vary too greatly from their natural ecological setting (individual cage housing versus group housing). Three general points emerge from these examinations. First, providing companionship may be a very potent way in which to promote psychological well-being in nonhuman primates; however, social living is not synonymous with well-being. The extent to which social housing promotes psychological well-being can vary across species and among individual members of the same species (for example, high- and low-ranking monkeys). Secondly, housing conditions can affect research outcomes in that group-housed animals may differ from individually housed animals in response to some manipulation. Social interaction may be a significant variable in regulating the biobehavioral responses of nonhuman primates to experimental manipulations. Finally, a larger number of socially housed subjects than individually housed subjects may be necessary for some biomedical research projects to yield adequate data analysis. Thus, social living has significant benefits and some potential costs not only for the animals themselves, but for the research enterprise.


Synaptic organization of the rat thalamus: a quantitative study.
First-order thalamic nuclei receive driving afferents from ascending pathways and transmit processed information to the cortex. Higher-order thalamic nuclei receive driver messages from layer 5 of cortex and transmit information from one cortical area to the other. The different types of axon terminals RL (round vesicles, large terminals), RS (round vesicles, small terminals) and F (flattened vesicles) and their synaptic junctions have been here compared in three first-order (ventrobasal, lateral geniculate and anteroventral) and three higher-order (posterior, lateral posterior and mediodorsal) thalamic nuclei of the rat. In the present study, the higher-order relays differ from first-order relays as in the cat, in having fewer driver terminals (RL) and synapses than do the first-order relays. However, the F terminals showed opposite ratios in the first versus higher-order thalamic nuclei. The majority of the terminals in all thalamic nuclei studied were RS terminals. The area measurements of the three types of terminals and synaptic lengths showed no significant differences between first and higher-order nuclei. The driver inputs represent the minority and the modulatory inputs represent the majority of the terminals and synapses in all thalamic nuclei. In conclusion, there is a relative paucity of driver inputs, whereas modulatory inputs establish more numerous synapses to achieve finer modulation.


Antibiotic resistance and Hly plasmids in serotypes of Escherichia coli associated with porcine enteric disease.
A total of 359 hemolytic Escherichia coli strains, representing eight pig pathogenic serotypes and isolated from pigs with enteric disease, was tested for transferable resistance to eight antibiotics. The co-transfer of plasmids controlling hemolysin production (Hly) with antibiotic resistance plasmids (R-factors) was evaluated. Transferable resistance to tetracycline, streptomycin, and/or sulfonamides was found in 47% of the total number of strains and 80% of the resistant ones. Chloramphenicol resistance was seldom seen. Co-transfer of Hly with R-factors occurred in 22.5% of the strains, generally to a degree excluding a genetic linkage. Stable coexistence of two R-factors in a cell was indicated by transfer patterns in 29 of the strains.


Engineering enhancement of immune responses to DNA-based vaccines in a prostate cancer model in rhesus macaques through the use of cytokine gene adjuvants.
DNA immunization is an important vaccination technique that is being explored as an immunotherapeutic strategy against a variety of infectious diseases as well as cancer. We have been investigating the utility of DNA-based vaccine strategy against prostate cancer. We have developed a DNA vaccine construct that encodes for the human prostate specific antigen (PSA) gene. PSA expression is limited to prostate cells, and the level of PSA expression is substantially increased in prostate cancer cells. This tissue specificity makes PSA a potential target for the development of immunotherapies against prostate cancer. A DNA-based PSA vaccine was used to elicit PSA-specific host immune responses in rodent and nonhuman primate models. In an effort to enhance the clinical utility of the DNA-based PSA vaccine, we also examined the use of cytokine gene adjuvants to modulate vaccine-induced immune responses in these animal models. We observed that pCPSA vaccine-induced humoral and cellular immune responses can be modulated through the coimmunization with cytokine genes in mice, and these enhancement effects on the PSA-specific cellular responses were extended in macaques. More specifically, coimmunization with interleukin (IL)-2 cDNA construct resulted in a significant enhancement of PSA-specific antibody responses in both mice and macaque models. In contrast, coinjection of IL-12 resulted in reduction of antibody responses in both models. In mice, the groups coimmunized with IL-2, IL-12, or IL-18 showed a dramatic increase in T helper cell proliferation over the results with pCPSA alone. These results support that further evaluation of this vaccination strategy to treat prostate cancer is warranted.


Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines.
Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of viral Spike S1 protein encoding mRNA incorporated in a lipid nanoparticle and stabilized by polyethylene glycol (PEG). The mRNA vaccines are novel in many respects, including cellular uptake and the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences, encoding the SARS-CoV-2 Spike protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to the induction of virus-neutralizing antibodies and cytotoxic T-lymphocytes, will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. The mRNA-based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG and potential presentation in the context of CD1 will be discussed. Adenovirus vector-based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.


Sporadic trichoepithelioma demonstrates deletions at 9q22.3.
Trichoepithelioma (TE) is a benign cutaneous tumor that originates from hair follicles and occurs either in multiple or solitary lesions. Multiple TE is transmitted as an autosomal dominant trait, and a region at 9p21 is thought to be involved in the tumorigenesis. Solitary TE occurs more commonly than multiple TE and is not inherited. Histologically, TE tumors contain horn cysts and abortive hair papillae. A basal cell carcinoma appearance in some or all regions of a TE tumor can happen. In sporadic basal cell carcinoma, frequent deletions at 9q22.3 (Drosophila patched gene) have occurred. The objective of this study is to test whether loss of heterozygosity (LOH) on either 9p21 or on chromosome 9q22.3 could be detected in archival sporadic TE. We studied 29 randomly selected cases of sporadic TE by microdissection and polymerase chain reaction using paraffin-embedded, formalin-fixed tissue specimens on glass slides. Analysis was performed with the polymorphic markers IFNA and D9S171 (9p21) as well as D9S15, D9S303, D9S287, and D9S252 (9q22.3). The LOH at 9q22.3 was identified in 14 (48%) of 29 cases with at least 1 marker, while LOH could not be demonstrated using the markers IFNA and D9S171 (9p21). The results show that the Drosophila patched gene LOH can be frequently identified in paraffin-embedded sporadic TE after routine processing and indicates a common gatekeeper mechanism for both TE and basal cell carcinoma.


An In Vitro Study of Chitosan-Coated Bovine Pericardium as a Dural Substitute Candidate.
Defects in the dura matter can be caused by head injury, and many cases require neurosurgeons to use artificial dura matter. Bovine pericardium is an option due to its abundant availability, adjustable size and characteristics, and because it has more collagen than porcine or equine pericardia. Nevertheless, the drawback of bovine pericardium is that it has a higher inflammatory effect than other synthetic dura matters. Chitosan has been shown to have a strong anti-inflammatory effect and has good tensile strength; thus, the idea was formulated to use chitosan as a coating for bovine pericardium. This study used decellularized bovine pericardial membranes with 0.5% sodium dodecyl sulphate and coatings containing chitosan at concentrations of 0.25%, 0.5%, 0.75%, and 1%. An FTIR test showed the presence of a C=N functional group as a bovine pericardium-chitosan bond. Morphological tests of the 0.25% and 0.5% chitosan concentrations showed standard pore sizes. The highest tensile strength percentage was shown by the membrane with a chitosan concentration of 1%. The highest degradation rate of the membrane was observed on the 7th and 14th days for 0.75% and 1% concentrations, and the lowest swelling ratio was observed for the 0.25% concentration. The highest level of cell viability was found for 0.75% chitosan. The bovine pericardium membrane with a 0.75% concentration chitosan coating was considered the optimal sample for use as artificial dura matter.


Endocrine cells in tumour-bearing lungs.
When hormones are detected in the serum of patients with bronchial carcinoma they are generally considered to originate from the tumour, but this may be not the only explanation. Pulmonary endocrine cells proliferate in lungs affected by non-neoplastic disease and their products are often demonstrable in the serum. The aim of this study was to examine the pulmonary endocrine systems of a series of tumour-bearing lungs to see whether any changes in them could possibly account for raised levels of pulmonary peptides in the blood. The morphology, number, distribution, and content of pulmonary endocrine cells in 30 pairs of tumour-bearing lungs from patients coming to necropsy with bronchial carcinoma were examined. These features were related to the pathology of the tumour and to other pathological changes present in the lungs, and compared with pulmonary endocrine cells in 10 pairs of control lungs from patients without pulmonary disease. Increased numbers of endocrine cells, often in the form of large abnormal aggregates, were present in 17 pairs of tumour-bearing lungs where they were associated not with the tumour but with non-tumoral pathology, especially inflammation and changes associated with cardiac failure. Appropriate and inappropriate peptides were identified within them. The possibility is raised that, in some subjects with bronchial carcinoma who have raised serum hormone levels, the source of these substances might be the endocrine cells in the diseased lung around the tumour.


Assessment of the genetic diversity of Mycobacterium tuberculosis esxA, esxH, and fbpB genes among clinical isolates and its implication for the future immunization by new tuberculosis subunit vaccines Ag85B-ESAT-6 and Ag85B-TB10.4.
The effort to develop a tuberculosis (TB) vaccine more effective than the widely used Bacille Calmette-Guérin (BCG) has led to the development of two novel fusion protein subunit vaccines: Ag85B-ESAT-6 and Ag85B-TB10.4. Studies of these vaccines in animal models have revealed their ability to generate protective immune responses. Yet, previous work on TB fusion subunit vaccine candidate, Mtb72f, has suggested that genetic diversity among M. tuberculosis strains may compromise vaccine efficacy. In this study, we sequenced the esxA, esxH, and fbpB genes of M. tuberculosis encoding ESAT-6, TB10.4, and Ag85B proteins, respectively, in a sample of 88 clinical isolates representing 57 strains from Ark, USA, and 31 strains from Turkey, to assess the genetic diversity of the two vaccine candidates. We found no DNA polymorphism in esxA and esxH genes in the study sample and only one synonymous single nucleotide change (C to A) in fbpB gene among 39 (44.3%) of the 88 strains sequenced. These data suggest that it is unlikely that the efficacy of Ag85B-ESAT-6 and Ag85B-TB10.4 vaccines will be affected by the genetic diversity of M. tuberculosis population. Future studies should include a broader pool of M. tuberculosis strains to validate the current conclusion.


CTCF and transcription influence chromatin structure re-configuration after mitosis.
During mitosis, transcription is globally attenuated and chromatin architecture is dramatically reconfigured. We exploited the M- to G1-phase progression to interrogate the contributions of the architectural factor CTCF and the process of transcription to genome re-sculpting in newborn nuclei. Depletion of CTCF during the M- to G1-phase transition alters short-range compartmentalization after mitosis. Chromatin domain boundary re-formation is impaired upon CTCF loss, but a subset of boundaries, characterized by transitions in chromatin states, is established normally. Without CTCF, structural loops fail to form, leading to illegitimate contacts between cis-regulatory elements (CREs). Transient CRE contacts that are normally resolved after telophase persist deeply into G1-phase in CTCF-depleted cells. CTCF loss-associated gains in transcription are often linked to increased, normally illegitimate enhancer-promoter contacts. In contrast, at genes whose expression declines upon CTCF loss, CTCF seems to function as a conventional transcription activator, independent of its architectural role. CTCF-anchored structural loops facilitate formation of CRE loops nested within them, especially those involving weak CREs. Transcription inhibition does not significantly affect global architecture or transcription start site-associated boundaries. However, ongoing transcription contributes considerably to the formation of gene domains, regions of enriched contacts along gene bodies. Notably, gene domains emerge in ana/telophase prior to completion of the first round of transcription, suggesting that epigenetic features in gene bodies contribute to genome reconfiguration prior to transcription. The focus on the de novo formation of nuclear architecture during G1 entry yields insights into the contributions of CTCF and transcription to chromatin architecture dynamics during the mitosis to G1-phase progression.


Structural and magnetic properties of the low-dimensional fluoride β-FeF3(H2O)2·H2O.
We have reinvestigated the crystal structure of the low-dimensional fluoride β-FeF3(H2O)2·H2O using high resolution neutron and X-ray diffraction data. Moreover we have studied the magnetic behavior of this material combining medium resolution and high flux neutron powder diffraction together with magnetic susceptibility measurements. This fluoride compound exhibits vertex-shared 1D Fe(3+) octahedral chains, which are extended along the c-axis. The magnetic interactions between adjacent chains involve super-superexchange interactions via an extensive network of hydrogen bonds. This interchain hydrogen bonding scheme is sufficiently strong to induce a long range magnetic order appearing below T = 20(1) K. The magnetic order is characterized by the propagation vector k = (0, 0, 1/2), giving rise to a strictly antiferromagnetic structure where the Fe(3+) spins are lying within the ab-plane. Magnetic exchange couplings extracted from magnetization measurements are found to be J∥/kb = -18 K and J⊥/kb = -3 K. These values are in good agreement with the neutron diffraction data, which show that the system became antiferromagnetically ordered at ca. TN = 20(1) K.


The Ashley Treatment: Improving Quality of Life or Infringing Dignity and Rights?
The 'Ashley treatment' (growth attenuation, removal of the womb and breasts buds of a severely disabled child) has raised much ethical controversy. This article starts from the observation that this debate suffers from a lack of careful philosophical analysis which is essential for an ethical assessment. I focus on two central arguments in the debate, namely an argument defending the treatment based on quality of life and an argument against the treatment based on dignity and rights. My analysis raises doubts as to whether these arguments, as they stand in the debate, are philosophically robust. I reconstruct what form good arguments for and against the treatment should take and which assumptions are needed to defend the according positions. Concerning quality of life (Section 2), I argue that to make a discussion about quality of life possible, it needs to be clear which particular conception of the good life is employed. This has not been sufficiently clear in the debate. I fill this lacuna. Regarding rights and dignity (section 3), I show that there is a remarkable absence of references to general philosophical theories of rights and dignity in the debate about the Ashley treatment. Consequently, this argument against the treatment is not sufficiently developed. I clarify how such an argument should proceed. Such a detailed analysis of arguments is necessary to clear up some confusions and ambiguities in the debate and to shed light on the dilemma that caretakers of severely disabled children face.


[Laser surgery for some forms of secondary posttraumatic glaucoma].
Zeiss Visulas YAG I Nd:YAG laser (Opton, Germany) was used in the treatment of 70 patients with three forms of secondary posttraumatic glaucoma (adhesive glaucoma with anterior-chamber adhesions and goniosynechias, adhesive glaucoma with aphakia-aniridia symptom complex, and aphakic malignant glaucoma). Laser synechiolysis was highly effective in patients with the first of the listed forms of glaucoma if the operation was performed as early as possible. The efficacy of hyaloidotomy, particularly peripheral, is confirmed; this modality in combination with drug therapy helps normalize intraocular pressure. The place of transpupillary laser hyaloidotomy in the treatment of aphakic malignant glaucoma is defined.


Importance of Shared Treatment Goal Discussions in Rheumatoid Arthritis-A Cross-Sectional Survey: Patients Report Providers Seldom Discuss Treatment Goals and Outcomes Improve When Goals Are Discussed.
Treat-to-target (T2T) and shared decision-making are valued features of current guidelines for rheumatoid arthritis (RA) management. Although T2T has demonstrated value for improving RA outcomes, implementation remains inconsistent and lacks standardization and procedures for including patient input. We sought to better understand the impact of shared decisions on T2T and how treatment goal discussions between patients and providers impact RA treatment improvement and satisfaction. An anonymous, web-based questionnaire was presented to United States residents aged 18 years or older with a self-reported diagnosis of RA by a medical professional with 28 questions regarding socio-demographics, RA disease activity (DA), diagnosis, treatments, outcomes, and goals. Analyses included descriptive statistics with χ2 and rank sum tests for comparisons. The questionnaire was completed by 907 people (mean age of 58 years; mean 11 years since diagnosis; 90% female). The majority (571; 63%) did not discuss RA treatment goals with providers. Patients engaging in treatment goal discussions with their providers were three times more likely to be satisfied with their treatment plans. Patients discussing treatment goals with their providers were more likely to have improved DA levels and 68% more likely to reach remission. A majority of patients with RA report having no treatment goal discussion with their providers; however, these discussions are associated with greater DA improvement and treatment satisfaction. Further research should seek understanding of how shared treatment goal discussions relate to successful RA management and explore the development of practical tools to implement them in regular clinic practice as part of a T2T regimen.


Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance.
Protection from acute lymphoblastic leukemia relapse in the central nervous system (CNS) is crucial to survival and quality of life for leukemia patients. Current CNS-directed therapies cause significant toxicities and are only partially effective. Moreover, the impact of the CNS microenvironment on leukemia biology is poorly understood. In this study we showed that leukemia cells associated with the meninges of xenotransplanted mice, or co-cultured with meningeal cells, exhibit enhanced chemoresistance due to effects on both apoptosis balance and quiescence. From a mechanistic standpoint, we found that leukemia chemoresistance is primarily mediated by direct leukemia-meningeal cell interactions and overcome by detaching the leukemia cells from the meninges. Next, we used a co-culture adhesion assay to identify drugs that disrupted leukemia-meningeal adhesion. In addition to identifying several drugs that inhibit canonical cell adhesion targets we found that Me6TREN (Tris[2-(dimethylamino)ethyl]amine), a novel hematopoietic stem cell-mobilizing compound, also disrupted leukemia-meningeal adhesion and enhanced the efficacy of cytarabine in treating CNS leukemia in xenotransplanted mice. This work demonstrates that the meninges exert a critical influence on leukemia chemoresistance, elucidates mechanisms of relapse beyond the well-described role of the blood-brain barrier, and identifies novel therapeutic approaches for overcoming chemoresistance.


The role of Ginkgo Folium on antitumor: Bioactive constituents and the potential mechanism.
Ginkgo biloba L. is a well-known and highly regarded resource in Chinese traditional medicine due to its effectiveness and safety. Ginkgo Folium, the leaf of Ginkgo biloba L., contains biologically active constituents with diverse pharmacological activities. Recent studies have shown promising antitumor effects of the bioactive constituents found in Ginkgo Folium against various types of cancer cells, highlighting its potential as a natural source of antitumor agents. Further research is needed to elucidate the underlying mechanisms and optimize its therapeutic potential. To provide a detailed understanding of the pharmacological activities of Ginkgo Folium and its potential therapeutic benefits for cancer patients. In this study, we conducted a thorough and systematic search of multiple online databases, including PubMed, Web of Science, Medline, using relevant keywords such as "Ginkgo Folium," "flavonoids," "terpenoids," "Ginkgo Folium extracts," and "antitumor" to cover a broad range of studies that could inform our review. Additionally, we followed a rigorous selection process to ensure that the studies included in our review met the predetermined inclusion criteria. The active constituents of Ginkgo Folium primarily consist of flavonoids and terpenoids, with quercetin, kaempferol, isorhamnetin, ginkgolides, and bilobalide being the major compounds. These active constituents exert their antitumor effects through crucial biological events such as apoptosis, cell cycle arrest, autophagy, and inhibition of invasion and metastasis via modulating diverse signaling pathways. During the process of apoptosis, active constituents primarily exert their effects by modulating the caspase-8 mediated death receptor pathway and caspase-9 mediated mitochondrial pathway via regulating specific signaling pathways. Furthermore, by modulating multiple signaling pathways, active constituents effectively induce G1, G0/G1, G2, and G2/M phase arrest. Among these, the pathways associated with G2/M phase arrest are particularly extensive, with the cyclin-dependent kinases (CDKs) being most involved. Moreover, active constituents primarily mediate autophagy by modulating certain inflammatory factors and stressors, facilitating the fusion stage between autophagosomes and lysosomes. Additionally, through the modulation of specific chemokines and matrix metalloproteinases, active constituents effectively inhibit the processes of epithelial-mesenchymal transition (EMT) and angiogenesis, exerting a significant impact on cellular invasion and migration. Synergistic effects are observed among the active constituents, particularly quercetin and kaempferol. Active components derived from Ginkgo Folium demonstrate a comprehensive antitumor effect across various levels and pathways, presenting compelling evidence for their potential in new drug development. However, in order to facilitate their broad and adaptable clinical application, further extensive experimental investigations are required to thoroughly explore their efficacy, safety, and underlying mechanisms of action.


Factors regulating the exchange of nutrients and drugs between lymph and blood in the small intestine.
An experimental design was developed to study the factors regulating the absorption of nutrients and drugs into the intestinal lymphatic system in normal and cirrhotic rats. Test compounds given via in situ jejunal luminal perfusion or systemic intravenous infusion were measured simultaneously in intestinal lymph, portal venous plasma and intestinal perfusate. Steady-state lymph plasma concentration ratios were used to compare the permeability characteristics of the intestinal mucosal-lymph and blood-lymph barriers. The absorption of compounds from the interstitial space into the intestinal lymphatic system is determined primarily by their permeability through the capillary of the portal circulation and by their lipid solubility; if a compound is too large to be absorbed into the portal circulation it is absorbed into the intestinal lymphatics.


A discipline-specific determination of high quality nursing care.
The purpose of this study is to establish a framework for defining quality of care based in nursing's unique body of knowledge through identification of nursing actions associated with high quality care. Nurses are legally liable and morally responsible for the quality of the care they provide to patients. Yet the meaning of 'high quality nursing care' remains ambiguous mainly because models used to define it are borrowed from other disciplines. Two frameworks, quality and nursing knowledge, guided the selection and review of this literature review. The third framework of learning domains, an educational theory, assisted in organizing the data gathered from the literature. Attributes of high quality nursing care as perceived by both patients and nurses are described. Despite a professed philosophy of holism and humanism, nursing relies heavily on the industrially derived structure-process-outcome model with current emphasis on outcomes. Patient outcomes are the product of the service nurses deliver and are appropriate as defining criteria only when care is being evaluated from the patient's perspective. Defining quality from the nursing profession's frame of reference focuses on evaluating the services provided; that is, nursing actions and behaviours, linked to the use of nursing knowledge. High quality nursing equates with competence in the cognitive, affective, and psychomotor domains.


[Chondrosarcoma of the larynx and laryngectomy. Apropos of 2 cases].
Two malignant tumors of cartilaginous origin are presented. Both demonstrated all histologic criteria of chondrosarcomas. Chondrosarcoma of the larynx seem to arise from hyaline cartilage, being the cricoid the mostly involved cartilage. The growth rate is very low, so that the first symptoms, as hoarseness or dyspnea, may be anodyne. The survival rates are directly related to histological grading. Chondrosarcoma are usually of low-grade malignancy. Local growth is predominant, metastasis has been described for high-grade types. Local recurrence may occur even after years. Surgery is the treatment of choice.