Association of polymorphisms in the human IFN-gamma and IL-4 gene with oral lichen planus: a study in an ethnic Chinese cohort.
Cytokines have an important role in the pathogenesis and disease progression of oral lichen planus (OLP). The aim of this study was to investigate the impact of gene polymorphisms of T helper cell subtype Th1 and Th2 cytokines, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), on OLP in an ethnic Chinese cohort. We investigated IFN-gamma gene (IFNG) and IL-4 gene (IL-4) polymorphisms in 151 patients with OLP and 143 healthy controls using the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. Each genotype was also validated by direct DNA sequencing methods to further guarantee the significance of our findings. The data revealed that there were highly significant increases in +874 IFNG2 genotype distributions and allele T frequencies in both the OLP patient group (p = 0.033, 0.003) and the more progressive subtype group (eOLP)(p = 0.013, 0.001) compared with those of normal controls There was no difference between the OLP patient and healthy control groups in frequencies of both the IL-4 allele (p = 0.053) and genotype (p = 0.197), although the frequencies of the IL4-590 C allele (p = 0.001) and the CC genotype (p = 0.024) in patients with nonerosive OLP (neOLP) were significantly greater than the corresponding values in the control group. Our study suggests that IFN-gamma and IL-4 gene polymorphisms seem to have a positive influence on disease susceptibility and progression of OLP in this ethnic Chinese cohort.


Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.
Fibrosis in multiple organs, including the liver, kidney, and lung, often occurs secondary to environmental exposure. Asbestos exposure is one important environmental cause of lung fibrosis. The mechanisms that mediate fibrosis is not fully understood, although mitochondrial oxidative stress in alveolar macrophages is critical for fibrosis development. Mitochondrial Ca2+ levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca2+ compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca2+ into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca2+ influx in alveolar macrophages from wild-type, but not MCU+/-, mice. MCU expression polarized macrophages to a profibrotic phenotype after exposure to asbestos, and the profibrotic polarization was regulated by MCU-mediated ATP production. Profibrotic polarization was abrogated when MCU was absent or its activity was blocked. Of more importance, mice that were deficient in MCU were protected from pulmonary fibrosis. Regulation of mitochondrial Ca2+ suggests that MCU may play a pivotal role in the development of fibrosis and could potentially be a therapeutic target for pulmonary fibrosis.-Gu, L., Larson-Casey, J. L., Carter, A. B. Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.


Disentangling density and temperature effects in the viscous slowing down of glassforming liquids.
We present a consistent picture of the respective role of density (rho) and temperature (T) in the viscous slowing down of glassforming liquids and polymers. Specifically, based in part upon a new analysis of simulation and experimental data on liquid ortho-terphenyl, we conclude that a zeroth-order description of the approach to the glass transition (in the range of experimentally accessible pressures) should be formulated in terms of a temperature-driven super-Arrhenius activated behavior rather than a density-driven congestion or jamming phenomenon. The density plays a role at a quantitative level, but its effect on the viscosity and the alpha-relaxation time can be simply described via a single parameter, an effective interaction energy that is characteristic of the high-T liquid regime; as a result, rho does not affect the "fragility" of the glassforming system.


The Effect of Triptolide in Rheumatoid Arthritis: From Basic Research towards Clinical Translation.
Triptolide (TP), a major extract of the herb Tripterygium wilfordii Hook F (TWHF), has been shown to exert potent pharmacological effects, especially an immunosuppressive effect in the treatment of rheumatoid arthritis (RA). However, its multiorgan toxicity prevents it from being widely used in clinical practice. Recently, several attempts are being performed to reduce TP toxicity. In this review, recent progress in the use of TP for RA, including its pharmacological effects and toxicity, is summarized. Meanwhile, strategies relying on chemical structural modifications, innovative delivery systems, and drug combinations to alleviate the disadvantages of TP are also reviewed. Furthermore, we also discuss the challenges and perspectives in their clinical translation.


Combat orthopaedics: a view from the trenches.
Approximately 70% of war wounds involve the musculoskeletal system, and military orthopaedic surgeons have assumed a pivotal role in the frontline treatment of these injuries in Iraq. Providing battlefield orthopaedic care poses special challenges; not only are many wounds unlike those encountered in civilian practice, but patients also must be triaged and treated in an austere and dangerous environment, undergo staged resuscitation and definitive surgery, and endure prolonged medical evacuation, often involving ground, helicopter, and fixed-wing transport across continents. Most orthopaedic wounds in Iraq are caused by exploding ordnance--frequently, improvised explosive devices, or IEDs. Because of advances in care, rapid medical evacuation, and modern body armor, many casualties have survived in Iraq who would not have done so in previous wars. Treatment of war wounds, many of which are devastating in the scope of soft-tissue and bony injury, requires a team approach using hypotensive resuscitation, damage-control orthopaedics, new or rediscovered techniques of hemostatic and intravenous hemorrhage control, vacuum-assisted wound closure, and advanced reconstruction. Current challenges include prevention of infection, a better understanding of heterotopic ossification as a sequela of blast injury, and the need for a comprehensive, joint service database that encompasses the multilevel spectrum of orthopaedic care.


Kidney transplant-related knowledge and influencing factors in Chinese kidney transplant candidates and recipients: A cross-sectional study.
To investigate the kidney transplantation knowledge of kidney transplant (KT) candidates and recipients, and to explore the related influencing factors. From March to July 2022, a total of 170 KT candidates and 270 KT recipients were investigated in two tertiary and Grade A hospitals in Hunan Province, China, using demographic questionnaires and the Kidney Transplant Understanding Tool (K-TUT). Multiple linear regression was used to explore the influencing factors of related knowledge of kidney transplantation. The scores of kidney transplantation knowledge of the two groups were 50.67 (Ranged: 0-63) and 52.79 (Ranged: 0-62), indicating a middle level of knowledge. Education level and whether they have received health education were significantly associated with the knowledge level of kidney transplantation in both KT candidates and recipients. In addition, age and fertility status were only significantly associated with the knowledge level of kidney transplantation in KT recipients. Our finding shows that the knowledge level of KT candidates and recipients is not optimistic, which suggests that healthcare providers should pay more attention to the health education of this population. In addition, future health education interventions should consider the education level, age, and fertility status factors affecting kidney transplantation knowledge in KT candidates and recipients.


FOXA2 suppresses gallbladder carcinoma cell migration, invasion, and epithelial-mesenchymal transition by targeting SERPINB5.
Gallbladder cancer (GBC), a highly malignant gastrointestinal tumor, lacks effective therapies. Foxhead box A2 (FOXA2) is a tumor suppressor that is poorly expressed in various human malignancies. This study aimed to ascertain FOXA2 expression in GBC and its relevance to tumor metastasis, and to elucidate its regulatory mechanism with epithelial-mesenchymal transition (EMT) as an entry point, in the hope of providing a potential therapeutic target for GBC. FOXA2 expression in GBC tissues was first detected using immunohistochemistry (IHC), followed by correlation analysis with clinicopathological characteristics and survival prognosis. Subsequently, the effects of FOXA2 on GBC cell migration and invasion, as well as EMT induction, were evaluated by scratch, Transwell, RT-PCR, and Western blot assays, together with animal experimentation. Ultimately, mRNA sequencing was carried out to identify the key downstream target genes of FOXA2 in controlling the EMT process in GBC cells, and dual-luciferase reporter and chromatin immunoprecipitation assays were used to determine its regulatory mechanism. FOXA2 was underexpressed in GBC tissues and inversely correlated with tumor node metastasis stage, lymph node metastasis, and poor patient prognosis. FOXA2 exerts suppressive effects on EMT and metastasis of GBC in vivo and in vitro. FOXA2 can impede GBC cell migratory and invasive functions and EMT by positively mediating serine protein kinase inhibitor B5 (SERPINB5) expression. FOXA2 directly binds to the SERPINB5 promoter region to stimulate its transcription, thereby modulating the migration and invasion behaviors of GBC cells as well as the EMT process, which might be an effective therapeutic target against GBC.


[Hospital care and school attendance. Experimental school attendance outside the hospital for children in a psychiatric department (author's transl)].
If school is a natural part of the world of childhood, hospital and disease may impose themselves. In that case, maintaining the child's relationship with the school environment becomes a problem. Schools have therefore been set up inside hospitals. The acceptance, by schools, of patients with chronic illness or incapacitation has been facilitated. We chose an intermediate answer in which, for a given child, the hospital and the school coexist, although they remain separate. Hospitalized children attend ordinary schools located near the hospital. Through the observations of three children, we describe the progression of our considerations about the effects of this practice. When a hospital department opens up to the outside world, both external and internal difficulties arise. We believe that the process by which this adventure is made possible and is carried out is part of the team work which gives the child, it's parents, and the medical staff, more autonomy, thereby helping the child to return to it's family.


Elevated Mitochondrial Reactive Oxygen Species and Cellular Redox Imbalance in Human NADPH-Oxidase-Deficient Phagocytes.
Chronic granulomatous disease (CGD) is caused by mutations in genes that encode the NADPH-oxidase and result in a failure of phagocytic cells to produce reactive oxygen species (ROS) via this enzyme system. Patients with CGD are highly susceptible to infections and often suffer from inflammatory disorders; the latter occurs in the absence of infection and correlates with the spontaneous production of inflammatory cytokines. This clinical feature suggests that NADPH-oxidase-derived ROS are not required for, or may even suppress, inflammatory processes. Experimental evidence, however, implies that ROS are in fact required for inflammatory cytokine production. By using a myeloid cell line devoid of a functional NADPH-oxidase and primary CGD cells, we analyzed intracellular oxidants, signs of oxidative stress, and inflammatory cytokine production. Herein, we demonstrate that phagocytes lacking a functional NADPH-oxidase, namely primary CGD phagocytes and a gp91phox-deficient cell line, display elevated levels of ROS derived from mitochondria. Accordingly, these cells, despite lacking the major source of cellular ROS, display clear signs of oxidative stress, including an induced expression of antioxidants and altered oxidation of cell surface thiols. These observed changes in redox state were not due to abnormalities in mitochondrial mass or membrane integrity. Finally, we demonstrate that increased mitochondrial ROS enhanced phosphorylation of ERK1/2, and induced production of IL8, findings that correlate with previous observations of increased MAPK activation and inflammatory cytokine production in CGD cells. Our data show that elevated baseline levels of mitochondria-derived oxidants lead to the counter-intuitive observation that CGD phagocytes are under oxidative stress and have enhanced MAPK signaling, which may contribute to the elevated basal production of inflammatory cytokines and the sterile inflammatory manifestations in CGD.


Impact of the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on offspring neurodevelopment: 5-year follow-up of a randomized controlled trial.
Evidence regarding the effect of n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on offspring's neurodevelopment is not conclusive. In this analysis, the effect of a reduced n-6:n-3 LCPUFA ratio in the diet of pregnant/lactating women (1.2 g n-3 LCPUFA together with an arachidonic acid (AA)-balanced diet between 15th wk of gestation-4 months postpartum vs control diet) on child neurodevelopment at 4 and 5 years of age was assessed. A child development inventory (CDI) questionnaire and a hand movement test measuring mirror movements (MMs) were applied and the association with cord blood LCPUFA concentrations examined. CDI questionnaire data, which categorizes children as 'normal', 'borderline' or 'delayed' in different areas of development, showed no significant evidence between study groups at 4 (n=119) and 5 years (n=130) except for the area 'letters' at 5 years of age (P=0.043). Similarly, the results did not strongly support the hypothesis that the intervention has a beneficial effect on MMs (for example, at 5 years: dominant hand, fast: adjusted mean difference, -0.08 (-0.43, 0.26); P=0.631). Children exposed to higher cord blood concentrations of docosahexaenoic acid, eicosapentaenoic acid and AA, as well as a lower ratio of n-6:n-3 fatty acids appeared to show beneficial effects on MMs, but these results were largely not statistically significant. Our results do not show clear benefits or harms of a change in the n-6:n-3 LCPUFA ratio during pregnancy on offspring's neurodevelopment at preschool age. Findings on cord blood LCPUFAs point to a potential influence on offspring development.


H3K27me3 may be associated with Oct4 and Sox2 in mouse preimplantation embryos.
As a core member of polycomb repressive complex 2, the transcription and enzyme activity of enhancer of zeste homolog 2 (Ezh2) is directly involved in the trimethylation of lysine 27 on histone H3. In this study, the fluorescence intensity of H3K27me3 in mouse in vivo morulae and blastocysts was compared by indirect immunofluorescence staining. We found that demethylation of H3K27me3 occurred during the blastocyst stage. Real-time polymerase chain reaction was performed to investigate Ezh2 expression in oocytes and in preimplantation embryos. Ezh2 expression peaked during the zygote stage and gradually decreased from the 2-cell stage, exhibiting an inverse pattern when compared with Oct4 and Sox2 mRNA in mouse preimplantation embryos. To understand the role of development-related genes on the transcription of mouse Ezh2, a promoter assay was performed in NIH/3T3 cells. Ezh2 expression was markedly suppressed by Oct4 and Sox2 alone in a dose-dependent manner, while Ezh2 promoter activity in co-transfection with Nanog, Klf-4, and c-Myc groups showed no significant change as compared with the control. Our data suggest that the demethylation of H3K27me3 is caused by the degressive expression and activity of Ezh2 in blastocysts, leading to increased expression of developmentally important transcription factors. We also observed negative effects of Oct4 and Sox2 on the transcription of Ezh2 and identified Oct4 and Sox2 as novel negative regulators of Ezh2 at the post-translation level in a mouse preimplantation embryo.


[An occupational acute poisoning incident of diethylene glycol monobutyl ether].
Objective: To analyze the causes and clinical characteristics of 9 cases of occupational acute poisoning with diethylene glycol monobutyl ether, and provide a basis for clinical diagnosis, treatment, prognosis, and prevention. Methods: The leakage accident of diethylene glycol monobutyl ether occurred in an electronic company in Janvary 2021, in Weihai City was analyzed. The clinical manifestations, laboratory examinations, diagnosis, treatment and prognosis of 9 cases of diethylene glycol monobutyl ether poisoning were summarized. Results: All 9 patients had moderate chemical eye burns and chemical conjunctivitis, and were immediately given symptomatic treatment. They fully recovered after 14 days. Conclusion: Patients who inhale diethylene glycol monobutyl ether for a short time have obvious eye burns, but early detection and timely treatment can achieve better prognosis.


Nutritional management of acute diarrhea: an appraisal of the alternatives.
Whether fasting during an episode of acute diarrhea is necessary or desirable has recently been questioned. The principal argument advanced for limited fasting is the avoidance of the consequences of malabsorption, namely acidosis, excessive fluid losses, depletion of the bile acid pool, and possible mucosal injury from unabsorbed foods. Advocates of continued feeding during acute diarrhea suggest that the practice will prevent deficits of intakes of protein and calories, maintain or stimulate repair of the intestinal mucosa, and sustain breast-feeding in the breast-fed infant. There are only a limited number of clinical studies that address the issue. Available evidence suggests that, in most cases, current practice should be modified to minimize food withdrawal.


Spatial and rotational quality assurance of 6DOF patient tracking systems.
External tracking systems used for patient positioning and motion monitoring during radiotherapy are now capable of detecting both translations and rotations. In this work, the authors develop a novel technique to evaluate the 6 degree of freedom 6(DOF) (translations and rotations) performance of external motion tracking systems. The authors apply this methodology to an infrared marker tracking system and two 3D optical surface mapping systems in a common tumor 6DOF workspace. An in-house designed and built 6DOF parallel kinematics robotic motion phantom was used to perform motions with sub-millimeter and subdegree accuracy in a 6DOF workspace. An infrared marker tracking system was first used to validate a calibration algorithm which associates the motion phantom coordinate frame to the camera frame. The 6DOF positions of the mobile robotic system in this space were then tracked and recorded independently by an optical surface tracking system after a cranial phantom was rigidly fixed to the moveable platform of the robotic stage. The calibration methodology was first employed, followed by a comprehensive 6DOF trajectory evaluation, which spanned a full range of positions and orientations in a 20 × 20 × 16 mm and 5° × 5° × 5° workspace. The intended input motions were compared to the calibrated 6DOF measured points. The technique found the accuracy of the infrared (IR) marker tracking system to have maximal root-mean square error (RMSE) values of 0.18, 0.25, 0.07 mm, 0.05°, 0.05°, and 0.09° in left-right (LR), superior-inferior (SI), anterior-posterior (AP), pitch, roll, and yaw, respectively, comparing the intended 6DOF position and the measured position by the IR camera. Similarly, the 6DOF RSME discrepancy for the HD optical surface tracker yielded maximal values of 0.46, 0.60, 0.54 mm, 0.06°, 0.11°, and 0.08° in LR, SI, AP, pitch, roll, and yaw, respectively, over the same 6DOF evaluative workspace. An earlier generation 3D optical surface tracking unit was observed to have worse tracking capabilities than both the IR camera unit and the newer 3D surface tracking system with maximal RMSE of 0.69, 0.74, 0.47 mm, 0.28°, 0.19°, and 0.18°, in LR, SI, AP, pitch, roll, and yaw, respectively, in the same 6DOF evaluation space. The proposed technique was found to be effective at evaluating the performance of 6DOF patient tracking systems. All observed optical tracking systems were found to exhibit tracking capabilities at the sub-millimeter and subdegree level within a 6DOF workspace.


Ginsenoside Rk3 Suppresses Hepatocellular Carcinoma Development through Targeting the Gut-Liver Axis.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Our previous reports showed that ginsenoside Rk3 provided excellent efficacy in alleviating the intestinal inflammatory response and protecting the liver, but its mechanism for HCC prevention remains to be explored. Here, the results suggested that Rk3 displayed potent antitumor effects against a dimethyl nitrosamine- and CCl4-induced HCC mouse model. Results revealed that Rk3 application inhibited liver injury, fibrosis, and cirrhosis. In parallel, Rk3 lowered the inflammatory response by decreasing the expression of inflammatory cytokines, inducing apoptosis, and blocking the cell cycle. Meanwhile, Rk3 effectively ameliorated the gut microbiota dysbiosis. Furthermore, correlation analysis revealed that the LPS-TLR4 signaling pathway, which was inhibited by Rk3, plays a key role in preventing HCC. To conclude, our research provides valuable insights into how Rk3 application targets the gut-liver axis and suppresses HCC development, suggesting that Rk3 might be a promising candidate for clinical treatment of HCC.


Effects of Experimental Sleep Restriction on Energy Intake, Energy Expenditure, and Visceral Obesity.
Although the consequences of sleep deficiency for obesity risk are increasingly apparent, experimental evidence is limited and there are no studies on body fat distribution. The purpose of this study was to investigate the effects of experimentally-induced sleep curtailment in the setting of free access to food on energy intake, energy expenditure, and regional body composition. Twelve healthy, nonobese individuals (9 males, age range 19 to 39 years) completed a randomized, controlled, crossover, 21-day inpatient study comprising 4 days of acclimation, 14 days of experimental sleep restriction (4 hour sleep opportunity) or control sleep (9 hour sleep opportunity), and a 3-day recovery segment. Repeated measures of energy intake, energy expenditure, body weight, body composition, fat distribution and circulating biomarkers were acquired. With sleep restriction vs control, participants consumed more calories (P = 0.015), increasing protein (P = 0.050) and fat intake (P = 0.046). Energy expenditure was unchanged (all P > 0.16). Participants gained significantly more weight when exposed to experimental sleep restriction than during control sleep (P = 0.008). While changes in total body fat did not differ between conditions (P = 0.710), total abdominal fat increased only during sleep restriction (P = 0.011), with significant increases evident in both subcutaneous and visceral abdominal fat depots (P = 0.047 and P = 0.042, respectively). Sleep restriction combined with ad libitum food promotes excess energy intake without varying energy expenditure. Weight gain and particularly central accumulation of fat indicate that sleep loss predisposes to abdominal visceral obesity. (Sleep Restriction and Obesity; NCT01580761).


Authoritarianism among border police officers, career soldiers, and airport security guards at the Israeli border.
Several personality theories focusing on specific personality variables involved in career choice and job satisfaction are based on the assumption that individuals choose certain career choices because they believe that they may be able to meet their emotional needs (J. L. Holland, 1977). The author of this study investigated the personality traits of border police officers, career soldiers, and airport security guards in Israel. The participants were 160 men--40 border policemen, 40 career soldiers, 40 airport security guards, and 40 control participants--who filled out a demographic questionnaire and a Hebrew version of the right-wing authoritarianism (RWA) shortened scale (B. Altemeyer, personal communication, February 2000). The present hypothesis predicted that the RWA scores of border police officers would be the highest, followed by those of career soldiers, airport security guards, and control participants, in that order. Statistically significant differences in RWA scores occurred between these groups in the predicted order, with the exception of the career soldiers' RWA scores, which did not significantly differ from those of the airport security guards.


Human allergy to environmental pet danders: a public health perspective.
The prevalence of human allergy to pet danders has increased rapidly over the past six decades, as a consequence of lifestyle changes that have enhanced ambient exposure to pet allergens. This is a problem of global public health importance, as the morbidity associated with allergic diseases disproportionately affects socio-economically disadvantaged populations, particularly children. Although the public often seeks advice from veterinary health-care professionals regarding healthy pet ownership practices, including strategies for reducing residential pet dander exposure, many misconceptions persist in the public domain regarding pet dander allergy, such as the belief that certain dog and cat breeds are 'hypoallergenic' due to their hair/coat type. This review considers the epidemiology of human exposure to the major cat and dog dander allergens, Fel d 1 and Can f 1 respectively, and the sensitization mechanisms to them, including the hygiene hypothesis and the putative role of bacterial endotoxin. The literature regarding primary and secondary exposures in different ambient environments is explored including threshold effects that influence allergen sensitization and elicitation of symptoms, and environmental intervention strategies that seek to reduce allergen exposure. Pet-specific factors, including the aetiopathogenesis of the several cat and dog allergens that have been characterized to the molecular level, individual animal characteristics that influence Fel d 1 and Can f 1 shedding, and pet-directed interventions intended to reduce allergen dispersal, are discussed.


A stigmatic gene confers interspecies incompatibility in the Brassicaceae.
Pre-zygotic interspecies incompatibility in angiosperms is a male-female relationship that inhibits the formation of hybrids between two species. Here, we report on the identification of STIGMATIC PRIVACY 1 (SPRI1), an interspecies barrier gene in Arabidopsis thaliana. We show that the rejection activity of this stigma-specific plasma membrane protein is effective against distantly related Brassicaceae pollen tubes and is independent of self-incompatibility. Point-mutation experiments and functional tests of synthesized hypothetical ancestral forms of SPRI1 suggest evolutionary decay of SPRI1-controlled interspecies incompatibility in self-compatible A. thaliana. Hetero-pollination experiments indicate that SPRI1 ensures intraspecific fertilization in the pistil when pollen from other species are present. Our study supports the idea that SPRI1 functions as a barrier mechanism that permits entrance of pollen with an intrinsic signal from self species.


Mineralocorticoid receptor antagonism prevents hedonic deficits induced by a chronic sodium appetite.
Our laboratory has reported that manipulations that provoke a robust sodium appetite (e.g., sodium depletion, deoxycorticosterone acetate) decrease lateral hypothalamic self-stimulation (LHSS) reward if rats are denied access to hypertonic saline solutions. The following studies investigated the interaction between chronic sodium appetite and the renin-angiotensin-aldosterone system on LHSS reward. In Experiment 1, animals treated with the diuretic furosemide (20 mg/kg) when denied access to saline exhibited an increase in the current required to produce 50% of the maximum LHSS response rate (ECu50) 48 hr after extracellular volume depletion. Furosemide-depleted rats that were allowed to drink 0.3 M saline after depletion, or that were treated with the selective mineralocorticoid receptor (MR) antagonist spironolactone, which significantly reduced sodium appetite, did not show ECu50 changes. In Experiment 2 chronic intracerebroventricular administration of the selective MR antagonist RU 28318 (10 microg/microl/hr) prevented decreases in the ECu50 induced by deoxycorticosterone acetate-no salt treatment. We conclude that an unresolved sodium appetite will reduce responding for rewards and that experimental manipulations that reduce sodium appetite (e.g., access to saline or blockade of MR) decrease hedonic deficits.


Waiting-time dependent non-equilibrium phase diagram of simple glass- and gel-forming liquids.
Under numerous circumstances, many soft and hard materials are present in a puzzling wealth of non-equilibrium amorphous states, whose properties are not stationary and depend on preparation. They are often summarized in unconventional "phase diagrams" that exhibit new "phases" and/or "transitions" in which time, however, is an essential variable. This work proposes a solution to the problem of theoretically defining and predicting these non-equilibrium phases and their time-evolving phase diagrams, given the underlying molecular interactions. We demonstrate that these non-equilibrium phases and the corresponding non-stationary (i.e., aging) phase diagrams can indeed be defined and predicted using the kinetic perspective of a novel non-equilibrium statistical mechanical theory of irreversible processes. This is illustrated with the theoretical description of the transient process of dynamic arrest into non-equilibrium amorphous solid phases of an instantaneously quenched simple model fluid involving repulsive hard-sphere plus attractive square well pair interactions.


Probability expression for changeable and changeless uncertainties: an implicit test.
"Everything changes and nothing remains still."We designed three implicit studies to understand how people react or adapt to a rapidly changing world by testing whether verbal probability is better in expressing changeable uncertainty while numerical probability is better in expressing unchangeable uncertainty. We found that the "verbal-changeable" combination in implicit tasks was more compatible than the "numerical-changeable" combination. Furthermore, the "numerical-changeless" combination was more compatible than the "verbal-changeless" combination. Thus, a novel feature called "changeability" was proposed to describe the changeable nature of verbal probability. However, numerical probability is a better carrier of changeless uncertainty than verbal probability. These results extend the domain of probability predictions and enrich our general understanding of communication with verbal and numerical probabilities. Given that the world around us is constantly changing, this "changeability" feature may play a major role in preparing for uncertainty.


The value of HDL genetics.
To review studies on hereditary disorders of high-density lipoprotein (HDL) metabolism and studies on HDL genetics in mice, which have both provided valuable insight into the pathways of this intriguing lipoprotein and moreover revealed targets to raise HDLc to reduce atherosclerosis. To date, as many as 11 genes are considered key players in the synthesis, maturation, conversion and/or catabolism of HDL. Five of these genes have been identified in humans, APOA1, LCAT, ABCA1, LIPC, and CETP, whereas the other six genes have been identified in mice, SCARB1, ABCG1, ATPB5, PLTP, LIPG and APOM. Genetic association studies are as yet the best line of evidence of the roles of the 'murine genes' in human HDL pathways. In addition to recent genetic association studies, a third section describes exciting news on six newly proposed HDL genes VNN1, GALNT2, MMAB/MVK, CTalpha, BMP-1 and SIRT1. This review provides a summary of the current literature on the genetics of HDL. New information from this research area may assist us in obtaining a better understanding of HDL biology and identifying novel pharmacological targets.


Dynamics and anchoring of heterochromatic loci during development.
Positioning a euchromatic gene near heterochromatin can influence its expression. To better understand expression-relevant changes in locus positioning, we monitored in vivo movement of centromeres and a euchromatic locus (with and without a nearby insertion of heterochromatin) in developing Drosophila tissue. In most undifferentiated nuclei, the rate of diffusion and step size of the locus is unaffected by the heterochromatic insertion. Interestingly, although the movement observed here is non directional, the heterochromatic insertion allows the flanking euchromatic region to enter and move within the heterochromatic compartment. This study also finds that a constraint on chromatin movement is imposed which is a factor of distance from the centric heterochromatic compartment. This restraint prevents the heterochromatic locus from moving away from the centric heterochromatin compartment. Therefore, because of the constraint, even distinct and non-random nuclear organizations can be attained from random chromatin movements. We also find a general constraint on chromatin movement is imposed during differentiation, which stabilizes changes in nuclear organization in differentiated nuclei.


Swimming Motility Reduces Deposition to Silica Surfaces.
The transport and fate of bacteria in porous media is influenced by physicochemical and biological properties. This study investigated the effect of swimming motility on the attachment of cells to silica surfaces through comprehensive analysis of cell deposition in model porous media. Distinct motilities were quantified for different strains using global and cluster-based statistical analyses of microscopic images taken under no-flow condition. The wild-type, flagellated strain DJ showed strong swimming as a result of the actively swimming subpopulation whose average speed was 25.6 μm/s; the impaired swimming of strain DJ77 was attributed to the lower average speed of 17.4 μm/s in its actively swimming subpopulation; and both the nonflagellated JZ52 and chemically treated DJ cells were nonmotile. The approach and deposition of these bacterial cells were analyzed in porous media setups, including single-collector radial stagnation point flow cells (RSPF) and two-dimensional multiple-collector micromodels under well-defined hydrodynamic conditions. In RSPF experiments, both swimming and nonmotile cells moved with the flow when at a distance ≥20 μm above the collector surface. Closer to the surface, DJ cells showed both horizontal and vertical movement, limiting their contact with the surface, while chemically treated DJ cells moved with the flow to reach the surface. These results explain how wild-type swimming reduces attachment. In agreement, the deposition in micromodels was also lowest for DJ compared with those for DJ77 and JZ52. Wild-type swimming specifically reduced deposition on the upstream surfaces of the micromodel collectors. Conducted under environmentally relevant hydrodynamic conditions, the results suggest that swimming motility is an important characteristic for bacterial deposition and transport in the environment.


Comprehensive analysis of the correlations of S100B with hypoxia response and immune infiltration in hepatocellular carcinoma.
S100B has been found to be dysregulated in many cancers including hepatocellular carcinoma (HCC). However, the functions of S100B and its underlying mechanisms in HCC remain poorly understood, especially in the tumor microenvironment. In this study, functions enrichment analysis indicated that S100B expression was correlated with hypoxia and immune responses. We found that hypoxia could induce S100B expression in an HIF-1α-dependent manner in HepG2 cells. Luciferase reporter and ChIP-qRCR assays demonstrated that HIF-1α regulates S100B transcription by directly binding to hypoxia-response elements (HREs) of the S100B promoter. Functionally, knockdown of S100B reduces hypoxia-induced HepG2 cell invasion and migration. Furthermore, GSVA enrichment results displayed that S100B and its co-expressed genes were positively correlated with EMT pathway in HCC. Additionally, GO/KEGG cluster analysis results indicated that co-expressed genes of S100B were involved in biological processes of immune response and multiple tumor immune-related signaling pathways in HCC. S100B expression was positively correlated with multiple immune cells tumor infiltration and associated with chemokines/chemokine receptors and immune checkpoint genes. Moreover, S100B is predominantly expressed in immune cells, especially NK (Natural Killer) cell. In addition, the hub genes of S100B co-expression and hypoxia response in HepG2 cell were also associated with immune cells infiltration in HCC. Taken together, these findings provide a new insight into the complex networks between hypoxia response and immune cells infiltration in tumor microenvironment of liver cancer. S100B maybe serve as a novel target for future HCC therapies.


GPKOW is essential for pre-mRNA splicing in vitro and suppresses splicing defect caused by dominant-negative DHX16 mutation in vivo.
Human GPKOW [G-patch (glycine-rich) domain and KOW (Kyrpides, Ouzounis and Woese) domain] protein contains a G-patch domain and two KOW domains, and is a homologue of Arabidopsis MOS2 and Saccharomyces Spp2 protein. GPKOW is found in the human spliceosome, but its role in pre-mRNA splicing remains to be elucidated. In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. Adding back recombinant GPKOW restored splicing to the depleted extract. In vivo, overexpression of GPKOW partially suppressed the splicing defect observed in dominant-negative DHX16 mutant expressing cells. Mutations at the G-patch domain greatly diminished the GPKOW-DHX16 interaction; however, the mutant was active in splicing and was able to suppress splicing defect. Mutations at the KOW1 domain slightly altered the GPKOW-RNA interaction, but the mutant was less functional in vitro and in vivo. Our results indicated that GPKOW can functionally impact DHX16 but that interaction between the proteins is not required for this activity.


Scientific Reproducibility in Biomedical Research: Provenance Metadata Ontology for Semantic Annotation of Study Description.
Scientific reproducibility is key to scientific progress as it allows the research community to build on validated results, protect patients from potentially harmful trial drugs derived from incorrect results, and reduce wastage of valuable resources. The National Institutes of Health (NIH) recently published a systematic guideline titled "Rigor and Reproducibility " for supporting reproducible research studies, which has also been accepted by several scientific journals. These journals will require published articles to conform to these new guidelines. Provenance metadata describes the history or origin of data and it has been long used in computer science to capture metadata information for ensuring data quality and supporting scientific reproducibility. In this paper, we describe the development of Provenance for Clinical and healthcare Research (ProvCaRe) framework together with a provenance ontology to support scientific reproducibility by formally modeling a core set of data elements representing details of research study. We extend the PROV Ontology (PROV-O), which has been recommended as the provenance representation model by World Wide Web Consortium (W3C), to represent both: (a) data provenance, and (b) process provenance. We use 124 study variables from 6 clinical research studies from the National Sleep Research Resource (NSRR) to evaluate the coverage of the provenance ontology. NSRR is the largest repository of NIH-funded sleep datasets with 50,000 studies from 36,000 participants. The provenance ontology reuses ontology concepts from existing biomedical ontologies, for example the Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT), to model the provenance information of research studies. The ProvCaRe framework is being developed as part of the Big Data to Knowledge (BD2K) data provenance project.


Childhood factors associated with mammographic density in adult women.
Growth and development factors could contribute to the development of breast cancer associated with an increase in mammographic density. This study examines the influence of certain childhood-related, socio-demographic and anthropometric variables on mammographic density in adult woman. The study covered 3574 women aged 45-68 years, participating in breast cancer-screening programmes in seven Spanish cities. Based on a craniocaudal mammogram, blind, anonymous measurement of mammographic density was made by a single radiologist, using Boyd's semiquantitative scale. Data associated with the early stages of life were obtained from a direct survey. Ordinal logistic regression and generalised linear models were employed to estimate the association between mammographic density and the variables covered by the questionnaire. Screening programme was introduced as a random effects term. Age, number of children, body mass index (BMI) and other childhood-related variables were used as adjustment variables, and stratified by menopausal status. A total of 811 women (23%) presented mammographic density of over 50%, and 5% of densities exceeded 75%. Our results show a greater prevalence of high mammographic density in women with low prepubertal weight (OR: 1.18; 95% CI: 1.02-1.36); marked prepubertal height (OR: 1.25; 95% CI: 0.97-1.60) and advanced age of their mothers at their birth (>39 years: OR: 1.28; 95% CI: 1.03-1.60); and a lower prevalence of high mammographic density in women with higher prepubertal weight, low birth weight and earlier menarche. The influence of these early-life factors may be explained by greater exposure to hormones and growth factors during the development of the breast gland, when breast tissue would be particularly susceptible to proliferative and carcinogenic stimulus.


Clinicopathological features and surgical options for synchronous colorectal cancer.
This study was conducted to investigate the clinicopathological features of synchronous cancers and treatment options according to their locations.Records of 8368 patients with colorectal cancer treated at our center between July 2003 and December 2010 were analyzed retrospectively. All synchronous colorectal cancer patients who underwent surgical treatment were included.Synchronous cancers were identified in 217 patients (2.6%). Seventy-nine patients underwent either total colectomy, subtotal colectomy, or total proctocolectomy; 116 underwent 1 regional resection, including local excision; and 22 underwent 2 regional resections. The mean age was 62 years, slightly higher than that for the single-cancer patients. Synchronous cancers were more common in male patients, more frequently located in the left colon, had more microsatellite instability-high status, and showed more advanced stage than single cancer. Extensive resection was mainly performed for synchronous cancers located in both the right and left colon. Two regional resections were performed for cancers in the right colon and rectum. There were no differences in complication rates or the occurrence of metachronous cancer between the 2-region resection and extensive resection groups. Eight years postoperatively, the mean number of daily bowel movements for these 2 groups were 1.9 and 4.3, respectively.We found that synchronous cancer was different from single cancer in terms of age, gender, location, and pathologic features. Synchronous colorectal cancer requires different treatment strategy according to the distribution of lesions. Comparison between the 2 regional resections and extensive resection approaches suggests that 2 regional resections are preferable.


Carcinosarcoma of the parotid: investigating its biology with morphoproteomics.
Carcinosarcoma of the parotid is a rare biphasic malignant neoplasm comprised of both carcinomatous and sarcomatous components representing approximately 0.4% of all malignant salivary gland neoplasms. We report a case of a 55-year-old Caucasian man who presented with a progressively enlarging left facial mass. Histopathological evaluation of the tumoral tissue revealed a high grade, mixed epithelial and mesenchymal malignant tumor, most consistent with a carcinosarcoma of the parotid. Morphoproteomic analysis was performed and revealed expression of secreted protein acidic and rich in cysteine (SPARC); glioma-associated oncogen protein 2 (Gli2); and phosphorylated signal transducer and activator of transcription (p-STAT3 [Tyr705]) in the carcinomatous and malignant mesenchymal components. These aforementioned markers have been linked to the epithelial-mesenchymal transition in which epithelial cells lose their characteristics and phenotypically become mesenchymal cells. This finding allows us to further understand the biology of the 2 cellular components of the carcinosarcoma as having a monoclonal origin.


Study of Janus Amphiphilic Graphene Oxide as a High-Performance Shale Inhibitor and Its Inhibition Mechanism.
Janus amphiphilic graphene oxide (JAGO), modified by dodecylamine on one side of graphene oxide (GO), was investigated for its novel use as a shale inhibitor. JAGO was synthesized by the Pickering emulsion template technology and was characterized by the Fourier-transform infrared spectra, UV-vis spectra, and transmission electron microscopy. Compared to KCl (5%), polyether diamine (2%), and pristine GO (0.2%), JAGO's highest shale recovery rate (75.2% at 80°C) and lowest swelling height of Mt-pellets (2.55 mm, 0.2%) demonstrated its excellent inhibitive property. Furthermore, JAGO acted as a perfect plugging agent and greatly reduced filtration loss. Based on the results of X-ray diffraction, contact angle measurements, and pressure transmission tests, we proposed that the 2D nano-sheet amphiphilic structure of JAGO, which enabled it to be effective both in chemical inhibition and physical plugging, was responsible for its remarkable inhibition performances.


Assessment of the sensory and physical limitations imposed by leprosy in a Brazilian Amazon Population.
Leprosy often results in sensory and physical limitations. This study aimed to evaluate these limitations using a quantitative approach in leprosy patients in Belém (Pará, Brazil). This epidemiological, cross-sectional study measured the sensory impairment of smell and taste through the use of a questionnaire and evaluated activity limitations of daily life imposed by leprosy through the Screening of Activity Limitation and Safety Awareness (SALSA) Scale. Data were collected from 84 patients and associations between the degree of disability and clinical and epidemiological characteristics were assessed. The majority of patients were men (64.3%), married (52.4%), age 31-40 years old (26.2%), had primary education (50%), and were independent laborers (36.9%). The multibacillary operational classification (81%), borderline clinical form (57.1%), and 0 degrees of physical disability (41.7%) were predominant. SALSA scores ranged from 17 to 59 points, and being without limitations was predominant (53.6%). The risk awareness score ranged from 0 to 8, with a score of 0 (no awareness of risk) being the most common (56%). Evaluation of smell and taste sensory sensitivities revealed that 70.2% did not experience these sensory changes. Patients with leprosy reactions were 7 times more likely to develop activity limitations, and those who had physical disabilities were approximately four times more likely to develop a clinical picture of activity limitations. Most patients showed no sensory changes, but patients with leprosy reactions were significantly more likely to develop activity limitations. Finally, further studies should be performed, assessing a higher number of patients to confirm the present results.


Breast conserving surgery and radiation in the treatment of operable breast cancer.
Breast conserving treatment (BCT) is an alternative to mastectomy, and prospective randomized trials have demonstrated that BCT and radical mastectomy result in similar actuarial survival rates. BCT should fulfil two criteria: (1) it should afford the same local control of disease as radical mastectomy, and (2) it should offer clear cosmetic and psychological advantages. This paper reviews the current status of BCT in the treatment of breast cancer. The choice of a narrow marginal tumor excision with aggressive radiation versus a wide resection with a small dose of radiation is discussed. Although the narrower marginal excisions, such as tumorectomy or lumpectomy provide the best cosmetic results, they may not provide adequate local control even when combined with aggressive irradiation. Wide resections such as quadrantectomy combined with a smaller dose of radiation, results in adequate local control, but less satisfactory cosmetic results. Although body image is better preserved by BCT, a clear enhancement of the psychological well being has yet to be established. Nevertheless, with further improvement in surgical, radiological and chemotherapeutic techniques, BCT likely will be the treatment of choice in more and more patients with operable breast cancer.


Photosynthetic signalling during high light stress and recovery: targets and dynamics.
The photosynthetic apparatus is one of the major primary sensors of the plant's external environment. Changes in environmental conditions affect the balance between harvested light energy and the capacity to deal with excited electrons in the stroma, which alters the redox homeostasis of the photosynthetic electron transport chain. Disturbances to redox balance activate photosynthetic regulation mechanisms and trigger signalling cascades that can modify the transcription of nuclear genes. H2O2 and oxylipins have been identified as especially prominent regulators of gene expression in response to excess light stress. This paper explores the hypothesis that photosynthetic imbalance triggers specific signals that target discrete gene profiles and biological processes. Analysis of the major retrograde signalling pathways engaged during high light stress and recovery demonstrates both specificity and overlap in gene targets. This work reveals distinct, time-resolved profiles of gene expression that suggest a regulatory interaction between rapidly activated abiotic stress response and induction of secondary metabolism and detoxification processes during recovery. The findings of this study show that photosynthetic electron transport provides a finely tuned sensor for detecting and responding to the environment through chloroplast retrograde signalling. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.


Nocturnal hypotension and ACE inhibitors.
Thirty essential hypertensive subjects had their BP measured by 24h ambulatory monitoring before (first placebo period) and after exposure to antihypertensive therapy with either enalapril (four weeks) or nitrendipine (six weeks). Similar measures of BP were obtained during a second placebo period intercalated between the two active drugs. The 24h averages of systolic and diastolic pressures were higher during placebo (148 +/- 3/91 +/- 1 mmHg, respectively) than during treatment periods. Four weeks of treatment with enalapril reduced arterial pressure to a 24h average of 137 +/- 1/86 +/- 1 mmHg while nitrendipine given for six weeks lowered BP to an average of 135 +/- 1/84 +/- 1 mmHg. The antihypertensive effect of the drugs was of a comparable magnitude (P > 0.05). In addition both drugs produced analogous reductions in BP during the day (07.00 to 23.00 h). In contrast, the nocturnal fall in BP was significantly greater during treatment with nitrendipine. Average systolic and diastolic pressures between 23.00 h and 07.00 h were 133 +/- 1 mmHg and 82 +/- 2 mmHg with enalapril compared with 129 +/- 3 mmHg (P < 0.01) and 77 +/- 3 mmHg (P < 0.01) with nitrendipine, respectively. These data suggest that antihypertensive agents show important differences in terms of their action on the mechanisms that regulate BP during sleep. Medications that amplify the otherwise physiological fall in BP during sleep may add risk to patients with impaired coronary vasodilator reserve owing to ventricular hypertrophy, coronary atherosclerosis, or both.


Health disparities from economic burden of diabetes in middle-income countries: evidence from México.
The rapid growth of diabetes in middle-income countries is generating disparities in global health. In this context we conducted a study to quantify the health disparities from the economic burden of diabetes in México. Evaluative research based on a longitudinal design, using cost methodology by instrumentation. For the estimation of epidemiological changes during the 2010-2012 period, several probabilistic models were developed using the Box-Jenkins technique. The financial requirements were obtained from expected case management costs by disease and the application of an econometric adjustment factor to control the effects of inflation. Comparing the economic impact in 2010 versus 2012 (p<0.05), there was a 33% increase in financial requirements. The total amount for diabetes in 2011 (US dollars) was $7.7 billion. It includes $3.4 billion in direct costs and $4.3 in indirect costs. The total direct costs were $.4 billion to the Ministry of Health (SSA), serving the uninsured population; $1.2 to the institutions serving the insured population (Mexican Institute for Social Security-IMSS-, and Institute for Social Security and Services for State Workers-ISSSTE-); $1.8 to users; and $.1 to Private Health Insurance (PHI). If the risk factors and the different health care models remain as they currently are in the analyzed institutions, health disparities in terms of financial implications will have the greatest impact on users' pockets. In middle-income countries, health disparities generated by the economic burden of diabetes is one of the main reasons for catastrophic health expenditure. Health disparities generated by the economic burden of diabetes suggests the need to design and review the current organization of health systems and the relevance of moving from biomedical models and curative health care to preventive and socio-medical models to meet expected challenges from diseases like diabetes in middle-income countries.


Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses.
To study the potential involvement of growth hormone-releasing hormone (GHRH) in the generation of growth hormone (GH) pulses in humans we have used a competitive antagonist to the GHRH receptor, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2(GHRH-Ant). Six healthy young men were given a bolus injection of GHRH-Ant 400 micrograms/kg body wt or vehicle at 2200 h and nocturnal GH concentrations were assessed by every 10-min blood sampling until 0800 h. Integrated total and pulsatile GH secretion were suppressed during GHRH-Ant treatment by 40 +/- 6 (SE) % and 75 +/- 5%, respectively. GHRH-Ant suppressed maximum (7.6 +/- 2.2 vs 1.8 +/- 0.5 micrograms/liter; P < 0.001) and mean (3.3 +/- 1.0 vs 1.1 +/- 0.2 micrograms/liter; P = 0.02) GH pulse amplitudes. There was no change in integrated nonpulsatile GH levels, pulse frequency, or interpulse GH concentration. GHRH-Ant 400 micrograms/kg also suppressed the GH responses to intravenous boluses of GHRH 0.33 micrograms/kg given 1, 6, 12, and 24 h later by 95, 81, 59, and 4%, respectively. In five healthy men, the responses to 10-fold larger GHRH boluses (3.3 micrograms/kg) were suppressed by 82 and 0%, 1 and 6 h after GHRH-Ant 400 micrograms/kg, respectively. These studies provide the first direct evidence that endogenous GHRH participates in the generation of spontaneous GH pulses in humans.


Advice on the medicolegal aspects of attendance at road accidents.
There is no strict legal obligation to render aid at the scene of an accident but in (rightly) doing so, one risks medicolegal consequences. An appropriate principle would be: 'A person is liable if he or she undertakes to perform a voluntary act and performs it improperly but not if he or she neglects to perform it'. No liability attaches to an error of judgement. The fear of litigation over negligence should never deter a medical practitioner from giving assistance in an emergency. The practitioner at an accident must observe the usual professional requirements: the 'duty of care' must be discharged by avoiding unreasonable risk, foreseeing the potential of the treatment and maintaining the standard of conduct of one's comparable peers. The doctor may not withdraw his care from the patient until it is possible to do so without increasing the risk to the patient or until he or she can do no more for the patient. (Thus, the best management is to arrange for rapid transfer to appropriate and adequate facilities.)


Proteinuria and progression of renal disease: therapeutic implications.
The relationship between proteinuria and progression of renal disease has long been an issue of debate. The present review deals with some of the recent publications on this topic. New concepts are emphasized: the possible causal role of proteinuria in the pathophysiology of progressive renal function loss, and the decrease in urinary protein loss at the beginning of renoprotective therapy as a predictor of renal function outcome during this treatment.


Customized growth charts for twin gestations to optimize identification of small-for-gestational age fetuses at risk of intrauterine fetal death.
Customized growth charts developed for singleton pregnancies have been shown to be more effective than population-based ones at identifying small-for-gestational age (SGA) fetuses at risk for intrauterine fetal death (IUFD). We sought to compare the association between SGA and IUFD in twins using customized growth charts designed for twin gestations compared to those designed for singletons. This was a retrospective cohort study using a database including singleton and twin pregnancies undergoing ultrasound examination between 16 and 20 weeks' gestation. After excluding preterm births < 34 weeks, congenital anomalies and stillbirths, we identified 51, 150 singleton births. Coefficients for significant physiological and pathological variables affecting birth weight for singletons were derived using backward stepwise multiple regression. The same process was repeated for twin births (1608 pairs), also adjusting for chorionicity. Customized growth charts for each pregnancy were derived using these two regression models for optimal birth weight at term and a proportionality equation. The association between SGA < 10(th) percentile, defined using the twin and singleton-customized charts, and IUFD were compared. Statistical analysis, including calculation of adjusted odds ratios (OR) for IUFD and screening accuracy using each chart, was performed. The derived coefficients for optimal birth weight for twins were different from those for singletons, with lower constants and root mean square error (3422 and 288.9, respectively, in twins vs 3543 and 416 in singletons). Among 3786 twin infants, IUFD was seen in 123 (3.2%). The numbers of fetuses identified as SGA were 575 (15.2%) and 504 (13.3%) by the singleton and twin charts, respectively. Fetuses classified as SGA by the twin-specific customized charts were at a significantly increased risk for IUFD (adjusted OR, 2.3 (95% CI, 1.4-3.5)), whereas those classified as SGA by the singleton-customized charts were not (adjusted OR, 1.2 (95% CI, 0.7-2.0)). Customized charts designed specifically for twins are more effective at identifying twin pregnancies at risk for IUFD than are those derived using singleton birth data.


Successful treatment of chronic cutaneous graft-versus-host-disease (GVHD) with penicillamine.
Chronic graft-versus-host-disease (GVHD) is a major complication of bone marrow transplantation. Until recently, little effective therapy has been available. We report a case of chronic cutaneous GVHD successfully treated with penicillamine.


[Discover potential inhibitors of 5-LOX and LTA4H from Rhei Radix et Rhizoma, Notopterygii Rhizoma et Radix and Genitana Macrophyllae Radix based on molecular simulation methods].
5-lipoxygenase (5-LOX) and leukotriene A4 hydrolase (LTA4H), as the major targets of 5-LOX branch in the arachidonic acid (AA) metabolic pathway, play an important role in the treatment of inflammation. Rhei Radix et Rhizoma, Notopterygii Rhizoma et Radix and Genitana Macrophyllae Radix have clear anti-inflammation activities. In this paper, the targets of 5-LOX and LTA4H were used as the research carrier, and Hiphop module in DS4.0 (Discovery studio) was used to construct ingredients database for preliminary screening of three traditional Chinese medicines based on target inhibitor pharmacophore, so as to obtain 5-LOX and LTA4H potential active ingredients. The ingredients obtained in initial pharmacophore screening were further screened by using CDOCKER module, and the screening rules were established based on the score of initial compound and the key amino acids to obtain 12 potential 5-LOX inhibitors and 7 potential LTA4H inhibitors. To be more specific, the potential 5-LOX inhibitors included 6 ingredients in Rhei Radix et Rhizoma, such as procyanidins B2-3,3'-O-double gallate and revandchinone 2; four ingredients in notopterygium, such as dodecanoic acid and so on. On the other hand, potential LTA4H inhibitors included revandchinone 1, revandchinone 4 in Rhei Radix et Rhizoma, tridecanoic acid, tetracosanoic acid and methyl eicosanoate in Notopterygii Rhizoma et Radix, montanic acid methyl ester and N-docosanoyl-O-aminobenzoate in Genitana Macrophyllae Radix and so on. The molecular simulation methods were highly efficient and time-saving to obtain the potential inhibitors of 5-LOX and LTA4H, which could provide assistance for discovering the chemical quality indicators of anti-inflammatory efficacy of three Chinese herbs, and may be helpful to promote the whole-process quality control of three Chinese herbs.


Psychological effects of living with rheumatoid arthritis.
Rheumatoid arthritis is a long-term inflammatory condition that can affect physical, psychological and social function. The condition is not curable - although drug therapy can be used to reduce inflammation - and patients often experience daily symptoms of joint pain and stiffness, fatigue and functional limitations. Patients may also experience psychological challenges. This article focuses on the psychological implications of living with rheumatoid arthritis, including reaction to diagnosis, anxiety and depression, body image, sexuality, self-esteem and social role. It aims to explore the role of the nurse in addressing these psychological challenges to optimise the physical and psychological status of each patient.


Development of self-cooperative nanochaperones with enhanced activity to facilitate protein refolding.
Regulating protein folding including assisting de novo folding, preventing misfolding and aggregation, and facilitating refolding of proteins are of significant importance for retaining protein's biological activities. Here, we report a mixed shell polymeric micelle (MSPM)-based self-cooperative nanochaperone (self-CO-nChap) with enhanced activity to facilitate protein refolding. This self-CO-nChap was fabricated by introducing Hsp40-mimetic artificial carriers into the traditional nanochaperone to cooperate with the Hsp70-mimetic confined hydrophobic microdomains. The artificial carrier facilitates transfer and immobilization of client proteins into confined hydrophobic microdomains, by which significantly improving self-CO-nChap's capability to inhibit unfolding and aggregation of client proteins, and finally facilitating refolding. Compared to traditional nanochaperones, the self-CO-nChap significantly enhances the thermal stability of horseradish peroxidase (HRP) epicyclically under harsher conditions. Moreover, the self-CO-nChap efficiently protects misfolding-prone proteins, such as immunoglobulin G (IgG) antibody from thermal denaturation, which is hardly achieved using traditional nanochaperones. In addition, a kinetic partitioning mechanism was devised to explain how self-CO-nChap facilitates refolding by regulating the cooperative effect of kinetics between the nanochaperone and client proteins. This work provides a novel strategy for the design of protein folding regulatory materials, including nanochaperones.


Course of mood and anxiety disorders during pregnancy and the postpartum period.
Because the onset of mood and anxiety disorders often occurs during the childbearing years, many women may be taking psychotropic medications for these disorders when they conceive. These medications easily diffuse across the placenta, and their impact on the fetus is of concern. But discontinuation may lead to relapse, in which case psychiatric symptoms may affect the fetus. Thoughtful treatment planning presents a dilemma to the clinician. Limited data suggest heightened vulnerability to relapse of mood and anxiety disorders in women during the postpartum period. Pregnancy appears to exacerbate symptoms of obsessive-compulsive disorder, while panic disorder patients may remain well after discontinuing medication. Future studies should address the prevalence and relapse rates of mood and anxiety disorders, particularly after medication discontinuation, among pregnant women.


Belowground biodiversity and ecosystem functioning.
Evidence is mounting that the immense diversity of microorganisms and animals that live belowground contributes significantly to shaping aboveground biodiversity and the functioning of terrestrial ecosystems. Our understanding of how this belowground biodiversity is distributed, and how it regulates the structure and functioning of terrestrial ecosystems, is rapidly growing. Evidence also points to soil biodiversity as having a key role in determining the ecological and evolutionary responses of terrestrial ecosystems to current and future environmental change. Here we review recent progress and propose avenues for further research in this field.


Recruitment of rural health care providers: a regional recruiter strategy.
Access to care in rural areas is a major problem. Despite more than 20% of the US population residing in these areas, only 9% of physicians practice there. Extensive research has documented multiple issues that affect where physicians decide to locate and maintain practices. Creative strategies have been used to influence these recruitment and retention decisions. An emerging strategy, borne out of the Robert Wood Johnson Foundation's Southern Rural Access Program (SRAP), effectively uses a targeted regional approach to assist rural communities and health care facilities in assessing health care needs and recruiting primary care providers. This article examines the issues surrounding recruitment and retention of primary care providers to rural areas and describes the experiences of the regional recruitment strategy in several states and in particular in the Mississippi Delta region of Arkansas. A case study approach is used to examine the targeted regional recruiter strategy in the Mississippi Delta region of Arkansas. The regional recruiter strategy, which combines traditional recruitment efforts with community development activities, has been successful in recruiting health care providers to rural communities. The cost-effective strategy can be easily replicated in other rural states. Community factors affect provider decisions on practice locations. Addressing community factors in recruitment efforts through community development activities may increase their success.


Using Landsat 8 imagery for remote monitoring of total phosphorus as a water quality parameter of irrigation ponds in Taiwan.
Monitoring water body quality parameters with high spatial and temporal resolutions is crucial because mitigation of pollution is usually costlier than early prevention/intervention. The existing monitoring methods for irrigation ponds in Taoyuan, Taiwan, are based on field measurements that have low spatial and temporal resolutions. In this study, using Landsat 8 satellite imagery, a multiple regression-derived relationship between the satellite band reflectance and the concentration of total phosphorus (TP) was established. The satellite imagery was atmospherically corrected with ACOLITE based on shortwave infrared (SWIR) bands. This method was used to select predictor variables in the multiple regression-derived equation based on forward selection of variables using a p value and variation inflation factor (VIF) threshold. The derived equation yielded a coefficient of determination (R2) of 0.67. The near-infrared band (band 5) was found to be most significant. The Landsat 8 imagery retrieved for two of the three pond studies included only a few pixels from the ponds because parts of the pond surfaces are covered by floating photovoltaic power plants. The TP concentrations resulting from the derived equation indicate the feasibility of using satellite remote sensing methods to monitor the water quality. The derived relationships are potentially applicable to extend the availability of temporal and spatial water quality data for these irrigation ponds.


Salicylic Acid Biosynthesis in Plants.
Salicylic acid (SA) is an important plant hormone that is best known for mediating host responses upon pathogen infection. Its role in plant defense activation is well established, but its biosynthesis in plants is not fully understood. SA is considered to be derived from two possible pathways; the ICS and PAL pathway, both starting from chorismate. The importance of both pathways for biosynthesis differs between plant species, rendering it hard to make generalizations about SA production that cover the entire plant kingdom. Yet, understanding SA biosynthesis is important to gain insight into how plant pathogen responses function and how pathogens can interfere with them. In this review, we have taken a closer look at how SA is synthesized and the importance of both biosynthesis pathways in different plant species.


Mobilization of Ca2+ from intracellular stores of pancreatic beta-cells by the calcium store blocker TMB-8.
TMB-8 has been used experimentally in many cell types, including endocrine cells, because of its ability to block the efflux of Ca2+ from intracellular stores without affecting influx. Unexpectedly, TMB-8 potentiates stimulated insulin release from pancreatic islets, a process believed to be dependent on the level of cytosolic Ca2+. In the present study, while having no effect on basal insulin release (in the presence of 2.8 mM glucose), TMB-8 (10, 30, and 100 microM) caused a concentration-dependent increase in 45Ca2+ efflux from 45Ca2+-preloaded islets. TMB-8 (100 microM) stimulated 45Ca2+ efflux even in the absence of extracellular Ca2+. In the presence of 5.6 mM glucose, TMB-8 (30 and 100 microM) potentiated insulin release and again increased 45Ca2+ efflux in a concentration-dependent manner. Similarly, insulin release stimulated by isobutylmethylxanthine (IBMX) was potentiated significantly, and IBMX-stimulated 45Ca2+ efflux was increased by the simultaneous introduction of 30 microM TMB-8. Thus, in pancreatic islets, TMB-8 appears to mobilize Ca2+ from intracellular stores, rather than inhibit the efflux as has been commonly accepted. In further studies, using insulin-secreting beta-cells of the RINm5F cell line, TMB-8 was shown to increase the cytosolic Ca2+ concentration in the presence and absence of extracellular Ca2+. This confirmed that mobilization of intracellular Ca2+ was occurring in the pancreatic beta-cell in response to TMB-8. Furthermore, a rise in cytosolic Ca2+ of not more than 10 nM (as induced with KCl) was found to mimick the effect of TMB-8 in conjunction with IBMX. No additional effect of TMB-8 to alter Ca2+ handling at the plasma membrane was found when 45Ca2+ uptake experiments were performed. Therefore, the paradoxical mobilization of beta-cell Ca2+ by TMB-8 appears to be a sufficient explanation for its potentiating effect on the rate of insulin secretion.


Predictors of positive health among a sample of South African adolescents.
Many studies that address adolescent health focus on risk behaviours, their predictors and outcomes, but few focus on positive health and its predictors. The aim of this study was to investigate aspects of adolescents' positive health (lack of emotional and somatic symptoms, positive subjective health and self-reported happiness), as predicted by adolescents' relationships with their parents and peers, and their perceptions of their school. The measure used was part of the Health Behaviour in School-age Children questionnaire. The sample included 515 South African Grade 8 secondary school students (51.8% Black, 48.2% White; 40.8% boys and 59.2% girls; M age 15.5 yr., SD = 1.6, range 14-18) chosen at random from three urban schools in Polokwane, Limpopo Province. Analysis indicated that positive perceptions of the school and parental relations were identified as significant and positive peer and siblings relationships as nonsignificant predictors for indicators of positive health.


Evaluation of genotoxicity of ampicillin and carbenicillin on human lymphocytes in vitro: chromosome aberrations, mitotic index, cell cycle kinetics, satellite associations of acrocentric chromosomes and sister chromatid exchanges.
A large number of drugs have been introduced into man's environment in recent years, many of which have been shown to have mutagenic, teratogenic and carcinogenic effects. Keeping in view the potential hazardous effects of drugs and chemicals, it is desirable to test new drugs for their genotoxic effects prior to widespread use. In the present investigation genetic effects of ampicillin and carbenicillin were studied in vitro in human lymphocytes using a number of end-points. These drugs were added at a range of concentrations and times during a 72h culture period. Concentrations corresponding to the plasma level after receiving therapeutic doses as well as concentrations higher than the plasma levels were examined. Neither drug affected the frequency of chromosome aberrations, satellite associations, mitotic index and cell turnover rate at plasma level concentrations. However, all these parameters were affected at higher concentrations. The frequency of SCEs was not increased with both the drugs irrespective of the concentrations or durations of treatment, suggesting that the mechanisms leading to the formation of SCEs and chromosome aberrations are different. Both ampicillin and carbenicillin were genetically non-toxic for the end points measured and non-clastogenic in vitro at therapeutic doses. However, previous studies have shown ampicillin to be clastogenic in vivo. For evaluation of genetic toxicity, drugs should be tested both in vitro and in vivo.


Design and simulation of a GST-based metasurface with strong and switchable circular dichroism.
Circular dichroism (CD) is required in the applications of biological detection, analytical chemistry, etc. Here, we numerically demonstrated large-range switchable CD by controlling the phase change of Ge2Sb2Te5 (GST) in a zigzag array. At the amorphous state of GST (a-GST), the strong and dual-waveband CD effects are realized via the selective excitations of electric, magnetic, and toroidal resonances. With the transition from a-GST to crystalline state GST, CD strengths are tailored dynamically in large ranges. In detail, the CD magnitudes change by about 0.93 and the modulation depths exceed 94% at dual wavebands. The strong CD effects and large-range switch capability in the GST-based metasurfaces will boost the development of active chiroptical devices.


COVID-19 risk, course and outcome in people with mental disorders: a systematic review and meta-analyses.
It has been suggested that people with mental disorders have an elevated risk to acquire severe acute respiratory syndrome coronavirus 2 and to be disproportionally affected by coronavirus disease 19 (COVID-19) once infected. We aimed to analyse the COVID-19 infection rate, course and outcome, including mortality and long COVID, in people with anxiety, depressive, neurodevelopmental, schizophrenia spectrum and substance use disorders relative to control subjects without these disorders. This study constitutes a preregistered systematic review and random-effects frequentist and Bayesian meta-analyses. Major databases were searched up until 27 June 2023. Eighty-one original articles were included reporting 304 cross-sectional and prospective effect size estimates (median n per effect-size = 114837) regarding associations of interest. Infection risk was not significantly increased for any mental disorder that we investigated relative to samples of people without these disorders. The course of COVID-19, however, is relatively severe, and long COVID and COVID-19-related hospitalization are more likely in all patient samples that we investigated. The odds of dying from COVID-19 were high in people with most types of mental disorders, except for those with anxiety and neurodevelopmental disorders relative to non-patient samples (pooled ORs range, 1.26-2.57). Bayesian analyses confirmed the findings from the frequentist approach and complemented them with estimates of the strength of evidence. Once infected, people with pre-existing mental disorders are at an elevated risk for a severe COVID-19 course and outcome, including long COVID and mortality, relative to people without pre-existing mental disorders, despite an infection risk not significantly increased.


Advantages of adding a course of tetracycline to single dose ampicillin and probenecid in the treatment of gonorrhoea.
Chlamydia trachomatis was reisolated from 11 of 12 men with gonorrhoea who had initially yielded chlamydiae and who had been treated with ampicillin and probenecid (AMP) only, but from none of five such men treated with ampicillin and probenecid followed by tetracycline (AMPT). These results correlated with the absence of postgonococcal urethritis (PGU) in the group treated with AMPT. C trachomatis was isolated or reisolated from 20 of 25 women after treatment with AMP, compared with none of 14 women treated with AMPT. We recommend the addition of a course of tetracycline to the routine single dose treatment for gonorrhoea in men and women.


[Population genetics processes in animal generations with brother X sister inbreeding and the absence of selection].
Fifteen distinct isolates of the progeny with a homozygosity ranging from 0 to 87.5% are formed in the model population of Drosophila melanogaster as a result of a systematic inbreeding "brother X sister". In these isolates 336 different variants are formed. The genetic regularity of segregation of each isolate variant for homozygosity in the subsequent generation of the progeny at such a mating type and the variability of mean homozygosity were determined.


Location, location, location: new insights into O-GalNAc protein glycosylation.
O-GalNAc glycosylation of proteins confers essential structural, protective and signaling roles in eumetazoans. Addition of O-glycans onto proteins is an extremely complex process that regulates both sites of attachment and the types of oligosaccharides added. Twenty distinct polypeptide GalNAc-transferases (GalNAc-Ts) initiate O-glycosylation and fine-tuning their expression provides a mechanism for regulating this action. Recently, a new mode of regulation has emerged where activation of Src kinase selectively redistributes Golgi-localized GalNAc-Ts to the ER. This relocalization results in a strong increase in the density of O-glycan decoration. In this review, we discuss how different mechanisms can regulate the number and the types of O-glycans decorating proteins. In addition, we speculate how Src-dependent relocation of GalNAc-Ts could play an important role in cancerous cellular transformation.


cAMP-mediated autophagy inhibits DNA damage-induced death of leukemia cells independent of p53.
Autophagy is important in regulating the balance between cell death and survival, with the tumor suppressor p53 as one of the key components in this interplay. We have previously utilized an in vitro model of the most common form of childhood cancer, B cell precursor acute lymphoblastic leukemia (BCP-ALL), to show that activation of the cAMP signaling pathway inhibits p53-mediated apoptosis in response to DNA damage in both cell lines and primary leukemic cells. The present study reveals that cAMP-mediated survival of BCP-ALL cells exposed to DNA damaging agents, involves a critical and p53-independent enhancement of autophagy. Although autophagy generally is regarded as a survival mechanism, DNA damage-induced apoptosis has been linked both to enhanced and reduced levels of autophagy. Here we show that exposure of BCP-ALL cells to irradiation or cytotoxic drugs triggers autophagy and cell death in a p53-dependent manner. Stimulation of the cAMP signaling pathway further augments autophagy and inhibits the DNA damage-induced cell death concomitant with reduced nuclear levels of p53. Knocking-down the levels of p53 reduced the irradiation-induced autophagy and cell death, but had no effect on the cAMP-mediated autophagy. Moreover, prevention of autophagy by bafilomycin A1 or by the ULK-inhibitor MRT68921, diminished the protecting effect of cAMP signaling on DNA damage-induced cell death. Having previously proposed a role of the cAMP signaling pathway in development and treatment of BCP-ALLs, we here suggest that inhibitors of autophagy may improve current DNA damage-based therapy of BCP-ALL - independent of p53.


Activation of human endothelial cells from specific vascular beds induces the release of a FVIII storage pool.
Although the liver is known to be the main site of factor VIII (FVIII) production, other organs are probably also important for the regulation of FVIII secretion. However, the study of the regulation of extrahepatic FVIII production has been hampered by the lack of definitive identification of human tissues able to secrete FVIII. Recent studies have shown that lung endothelial cells can synthesize FVIII. We therefore studied the production of FVIII by endothelial cells purified from other vascular beds. Because physiologic stress results in a rapid elevation of FVIII, we also investigated whether endothelial cells can store FVIII and secrete it after treatment with agonists. Microvascular endothelial cells from lung, heart, intestine, and skin as well as endothelial cells from pulmonary artery constitutively secreted FVIII and released it after treatment with phorbol-myristate acetate and epinephrine. By contrast, endothelial cells from the aorta, umbilical artery and umbilical vein did not constitutively secrete FVIII or release it after treatment with agonists, probably because of a lack of FVIII synthesis. Extrahepatic endothelial cells from certain vascular beds therefore appear to be an important FVIII production and storage site with the potential to regulate FVIII secretion in chronic and acute conditions.


Educational commission for foreign medical graduates certification and specialty board certification among graduates of the Caribbean medical schools.
To determine the variability among Caribbean medical schools in the performance of their students against markers of quality. The Educational Commission for Foreign Medical Graduates (ECFMG) database and the American Medical Association (AMA) Masterfile were linked. Analyses were restricted to ECFMG applicants, from 1980 to 2000, who attended the 12 Caribbean medical schools that produced 200 or more U.S. International Medical School Graduates (USIMGs). The schools produced 17,049 USIMG (48% of all USIMGs) and 5,840 non-USIMG (5% of all non-USIMGs) applicants for ECFMG certification. By school, the ECFMG certification rate ranged from 28% to 86% for USIMGs and from 27% to 82% for non-USIMGs. Specialty Board certification for graduates of these schools also varied widely. Medical schools in the Caribbean play an increasingly important role in supplying the U.S. workforce. There is considerable variability among them, both in the numbers of physicians they produce and the performance of their students against indicators of quality such as ECFMG and specialty Board certification.


In Vivo Two-photon Imaging of Megakaryocytes and Proplatelets in the Mouse Skull Bone Marrow.
Platelets are produced by megakaryocytes, specialized cells located in the bone marrow. The possibility to image megakaryocytes in real time and their native environment was described more than 10 years ago and sheds new light on the process of platelet formation. Megakaryocytes extend elongated protrusions, called proplatelets, through the endothelial lining of sinusoid vessels. This paper presents a protocol to simultaneously image in real time fluorescently labeled megakaryocytes in the skull bone marrow and sinusoid vessels. This technique relies on a minor surgery that keeps the skull intact to limit inflammatory reactions. The mouse head is immobilized with a ring glued to the skull to prevent movements from breathing. Using two-photon microscopy, megakaryocytes can be visualized for up to a few hours, enabling the observation of cell protrusions and proplatelets in the process of elongation inside sinusoid vessels. This allows the quantification of several parameters related to the morphology of the protrusions (width, length, presence of constriction areas) and their elongation behavior (velocity, regularity, or presence of pauses or retraction phases). This technique also allows simultaneous recording of circulating platelets in sinusoid vessels to determine platelet velocity and blood flow direction. This method is particularly useful to study the role of genes of interest in platelet formation using genetically modified mice and is also amenable to pharmacological testing (study the mechanisms, evaluating drugs in the treatment of platelet production disorders). It has become an invaluable tool, especially to complement in vitro studies as it is now known that in vivo and in vitro proplatelet formation rely on different mechanisms. It has been shown, for example, that in vitro microtubules are required for proplatelet elongation per se. However, in vivo, they rather serve as a scaffold, elongation being mainly promoted by blood flow forces.


Characterization of Lgr5+ Progenitor Cell Transcriptomes after Neomycin Injury in the Neonatal Mouse Cochlea.
Lgr5+ supporting cells (SCs) are enriched hair cell (HC) progenitors in the cochlea. Both in vitro and in vivo studies have shown that HC injury can spontaneously activate Lgr5+ progenitors to regenerate HCs in the neonatal mouse cochlea. Promoting HC regeneration requires the understanding of the mechanism of HC regeneration, and this requires knowledge of the key genes involved in HC injury-induced self-repair responses that promote the proliferation and differentiation of Lgr5+ progenitors. Here, as expected, we found that neomycin-treated Lgr5+ progenitors (NLPs) had significantly greater HC regeneration ability, and greater but not significant proliferation ability compared to untreated Lgr5+ progenitors (ULPs) in response to neomycin exposure. Next, we used RNA-seq analysis to determine the differences in the gene-expression profiles between the transcriptomes of NLPs and ULPs from the neonatal mouse cochlea. We first analyzed the genes that were enriched and differentially expressed in NLPs and ULPs and then analyzed the cell cycle genes, the transcription factors, and the signaling pathway genes that might regulate the proliferation and differentiation of Lgr5+ progenitors. We found 9 cell cycle genes, 88 transcription factors, 8 microRNAs, and 16 cell-signaling pathway genes that were significantly upregulated or downregulated after neomycin injury in NLPs. Lastly, we constructed a protein-protein interaction network to show the interaction and connections of genes that are differentially expressed in NLPs and ULPs. This study has identified the genes that might regulate the proliferation and HC regeneration of Lgr5+ progenitors after neomycin injury, and investigations into the roles and mechanisms of these genes in the cochlea should be performed in the future to identify potential therapeutic targets for HC regeneration.


Asymmetric Post-Traumatic Knee Arthritis Is Closely Correlated With Both Severity and Time for Lower Limb Coronal Plane Malalignment.
Mechanical alignment of the lower limbs has been suggested to cause abnormal uneven loading across the compartments at the knee, but its contribution to the initiation and progression of arthritis remains controversial. This study aimed to establish whether malalignment of the lower limb after trauma is associated with worsened arthritis scores in the theoretically overloaded compartment, and if arthritis scores continuously correlate with the degree of malalignment and time with deformity. After screening 1160 X-rays, 60 patients were identified with long-leg radiographs > 2 years after fracture. Measurement of mechanical axis deviation (MAD) divided into groups of varus malalignment (n = 16, >16 mm), valgus (n = 25, <0 mm), and normal alignment (n = 19). Alignment and bilateral knee compartmental arthritis scores were recorded by three clinicians, compared via analysis of variance and assessed with linear regression against time since injury using MAD as a covariate. In varus and valgus malalignment, there was a greater mean arthritis score in the "overloaded" compartment compared to the contralateral side, with varus medial Osteoarthritis Research Society International (OARSI) scores 5.17 ± 2.91 vs 3.50 ± 2.72 (P = 0.006) and Kellegren-Lawrence scores 2.65 ± 1.19 vs 1.79 ± 1.24 (P ≤ 0.001). In a linear regression model, OARSI arthritis score was significantly associated with absolute MAD (0.6/10 mm MAD, P < 0.001) and time (0.7/decade, P ≤ 0.001). Malalignment consistently results in more advanced arthritis scores in the overloaded compartment, most likely related to abnormal loading across the knee. Severity of arthritis using OARSI grading continuously correlates with degree of malalignment and time with deformity after post-traumatic malunion.


Surgical treatment of hand disorders in Farber's disease: a case report.
Farber's disease is a rare autosomal recessive disorder caused by a deficiency of acid ceramidase activity whose symptoms include hoarseness, subcutaneous nodules, and painful swollen and contracted joints. This case report focuses on hand abnormalities and surgical treatment of hand disorders in Farber's disease. A 9-year-old girl had occasional painful locking of the metacarpophalangeal joints of the middle fingers and severe tenderness of the dorsal aspect of the wrists. Resection of several nodules within the metacarpophalangeal joint and of a nodule that was firmly attached to the extensor pollicis longus tendon beneath the extensor retinaculum relieved pain and enabled the patient to perform daily activities.


Lectin histochemistry of glycolipid storage diseases on frozen and paraffin-embedded tissue sections.
Lectin histochemical studies were performed on frozen and paraffin-embedded brain tissue sections from six cases of galactosylceramide lipidosis (i.e., globoid cell leukodystrophy, or Krabbe's disease) in Twitcher mice and one case of canine infantile GM1-gangliosidosis. The globoid cells in Krabbe's disease stained with Ricinus communis agglutinin-I (RCA-I), peanut agglutinin (PNA), and Bandeirea simplicifolia agglutinin-I (BS-I) in frozen sections. However, paraffin sections and frozen sections pretreated with chloroform-methanol or xylene, from the same animals, stained with Concanavlia ensiformis agglutinin (ConA), wheat germ agglutinin (WGA), and succinylated-WGA (S-WGA), in addition to staining with RCA-I, PNA, and BS-I. The affected neurons of canine infantile GM1-gangliosidosis stained only with RCA-I in frozen sections. In paraffin sections, however, these cells were negative with RCA-I but positive with BS-I, ConA, Dolichos biflorus agglutinin (DBA), soybean agglutinin (SBA) and Ulex europaeus agglutinin (UEA-I) in paraffin sections. These results indicate that in paraffin processing of glycolipid storage disease tissue, some lectin receptors are lost and others are unmasked. The retained receptors can be stained with specific lectins and could serve as markers to characterize and differentiate among the various glycolipid storage diseases.


Introduction to statistical surveys of health science libraries.
The series of studies by the Committee on Surveys and Statistics of MLA presents the first comprehensive statistical picture of American health science libraries. These studies fill a serious information gap, and constitute a solid base for both present planning and historical record.


Acidically oxidized carbon cloth: a novel metal-free oxygen evolution electrode with high catalytic activity.
The efficiency of many energy storage technologies is limited by the sluggish kinetics of the oxygen evolution reaction (OER) and it is thus of great importance to develop highly active OER electrocatalysts made from earth-abundant elements. In this communication, we report a novel metal-free oxygen evolution electrode with high catalytic activity and stability through simple acidic oxidation of commercially available carbon cloth (CC). The resulting acidically oxidized CC exhibits an overpotential of 328 mV and a Tafel slope of 82 mV dec(-1) with 100% Faradaic efficiency. This electrode needs an overpotential of 477 mV to afford a current density of 10 mA cm(-2) and maintains its catalytic activity for at least 24,000 s. It offers us a low-cost flexible electrocatalytic electrode for device integration toward water splitting and rechargeable metal-air battery applications.


Synthetic Glycans Reveal Determinants of Antibody Functional Efficacy against a Fungal Pathogen.
Antibodies play a vital role in the immune response to infectious diseases and can be administered passively to protect patients. In the case of Cryptococcus neoformans, a WHO critical priority fungal pathogen, infection results in antibodies targeting capsular glucuronoxylomannan (GXM). These antibodies yield protective, non-protective, and disease-enhancing outcomes when administered passively. However, it was unknown how these distinct antibodies recognized their antigens at the molecular level, leading to the hypothesis that they may target different GXM epitopes. To test this hypothesis, we constructed a microarray containing 26 glycans representative of those found in highly virulent cryptococcal strains and utilized it to study 16 well-characterized monoclonal antibodies. Notably, we found that protective and non-protective antibodies shared conserved reactivity to the M2 motif of GXM, irrespective of the strain used in infection or GXM-isolated to produce a conjugate vaccine. Here, only two antibodies, 12A1 and 18B7, exhibited diverse trivalent GXM motif reactivity. IgG antibodies associated with protective responses showed cross-reactivity to at least two GXM motifs. This molecular understanding of antibody binding epitopes was used to map the antigenic diversity of two Cryptococcus neoformans strains, which revealed the exceptional complexity of fungal capsular polysaccharides. A multi-GXM motif vaccine holds the potential to effectively address this antigenic diversity. Collectively, these findings underscore the context-dependent nature of antibody function and challenge the classification of anti-GXM epitopes as either "protective" or "non-protective".


Activin A stimulates the proliferation and differentiation of cardiac fibroblasts via the ERK1/2 and p38-MAPK pathways.
Activin A is a key regulator of cardiac fibrosis. However, little is known about the mechanisms by which it contributes to cardiac fibrosis. Our study explored the effects of activin A on proliferation and differentiation of adult rat cardiac fibroblasts (CFs) via the activin A receptor, activin receptor-like kinase 4 (ALK4). CF proliferation was measured by CCK8 and EdU assays, while differentiation, fibrosis and signaling were measured by western blot analysis of α-smooth muscle actin, collagen type I, phosphorylated extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (p38-MAPK) expression. Activin A levels were measured by ELISA and western blot analysis. We demonstrated that CFs express activin A and its expression was significantly enhanced by angiotensin II (Ang II), but follistatin (activin A inhibitor) significantly reversed Ang II-induced activin A upregulation, CF proliferation, differentiation, collagen type I expression as well as ERK1/2 and p38-MAPK pathways activation. Conversely, recombinant activin A largely increased these parameters in both the presence and absence of Ang II. Interestingly, p38-MAPK (SB203580) and ALK4 (SB431542) inhibitors significantly reduced all activin A-mediated responses; however, an ERK1/2 inhibitor (PD98059) could only significantly reduce CF proliferation and collagen type I expression but not differentiation. Importantly, the most significant effects were observed in the presence vs. absence of Ang II. Thus, activin A promotes basal and Ang II-induced CF proliferation and differentiation via ALK4, and the effects are partly mediated through the ERK1/2 and p38-MAPK pathways. These data suggest that activin A is a potential therapeutic target for cardiac fibrosis.