Miracle-dz/UniFAR-FTUs huggingface dataset:
Klotho Regulates Retinal Pigment Epithelial Functions and Protects Against Oxidative Stress

The retinal pigment epithelium (RPE) is a highly specialized CNS tissue that plays crucial roles in retinal homeostasis. Age-related morphological changes in the RPE have been associated with retinal degenerative disorders; our understanding of the underlying molecular mechanisms, however, remains incomplete. Here we report on a key role of Klotho (Kl), an aging-suppressor gene, in retinal health and RPE physiology. Kl−/− mice show RPE and photoreceptor degeneration, reduced pigment synthesis in the RPE, and impaired phagocytosis of the outer segment of the photoreceptors. Klotho protein (KL) is expressed in primary cultured human RPE, and regulates pigment synthesis by increasing the expression of MITF (microphthalmia transcription factor) and TYR (tyrosinase), two pivotal genes in melanogenesis. Importantly, KL increases phagocytosis in cultured RPE by inducing gene expression of MERTK/AXL/TYRO3. These effects of KL are mediated through cAMP-PKA-dependent phosphorylation of transcription factor CREB. In cultured human RPE, KL increases the l-3,4-dihydroxyphenylalanine synthesis and inhibits vascular endothelial growth factor (VEGF) secretion from basal membrane by inhibiting IGF-1 signaling and VEGF receptor 2 phosphorylation. KL also regulates the expression of stress-related genes in RPE, lowers the production of reactive oxygen species, and thereby, protects RPE from oxidative stress. Together, our results demonstrate a critical function for KL in mouse retinal health in vivo, and a protective role toward human RPE cells in vitro. We conclude that KL is an important regulator of RPE homeostasis, and propose that an age-dependent decline of KL expression may contribute to RPE degeneration and retinal pathology.
Effect of CD80 and CD86 blockade and anti‐interleukin‐12 treatment on mouse acute graftversus‐host disease

We investigated the efficacy of a combination of anti‐CD80 and CD86 (CD80 + 86) monoclonal antibodies (mAb), anti‐interleukin (IL)‐12 mAb, or both, for prophylaxis in a mouse acute graft‐versus‐host‐disease (GVHD) model. The treatment with a combination of anti‐CD80 + 86 mAb efficiently reduced the lethality of GVHD, whereas mAb against either CD80 or CD86 alone had an effect. A delay in lymphocyte reconstitution and GVHD‐associated histological changes in organs was observed at 30 days post‐bone marrow transplantation (BMT) even in the anti‐CD80 + 86 mAb‐treated mice, although these manifestations were resolved by 100 days. In vitro, host alloantigen‐specific T cell proliferative responses and generation of CTL were significantly reduced by anti‐CD80 + 86 treatment. Furthermore, anti‐CD80 + 86 mAb preferentially inhibited the production of interferon (IFN)‐γ, but not IL‐4 and IL‐10, when cultures were assayed at 21 days. Although the anti‐IL‐12 mAb treatment alone inhibited the generation of cytotoxic T lymphocytes and IFN‐γ production in vitro, administration of anti‐IL‐12 mAb in vivo reversed the beneficial effects of anti‐CD80 + 86 treatment on host survival post‐BMT. The adverse effect of anti‐IL‐12 treatment seems to result from impairment of natural immunity and hematopoiesis, rather than as a consequence of an incomplete blockade of T helper (Th)1 responses. Our results suggest that the prevention of GVHD‐induced death results from the efficient blockade of Th1 cell activation by the anti‐CD80 + 86 treatment. However, further treatment is required for a complete prevention of GVHD, which seems to be partly mediated by Th2 cells.
Evaluating the Role of Health Informatics Professionals in Saudi Arabia: The Need for Collaboration

Saudi health authorities have acknowledged the role of health informatics professionals in improving the quality of medical services in Saudi Arabia. Different academic programs have been launched by different universities and medical colleges to produce qualified Saudi health informatics professionals. To date, there are no studies that have explained the role of health informaticians and their contribution towards the development of the Saudi health information infrastructure. In this study, the authors clarify health informatics practices and the different skills and job activities accomplished by health informaticians. With the growth in the number of Health Informatics programs within the country, there is a need to identify the current and future of HI professionals and to specify and clearly define the type of job titles describing health informatics roles. The Saudi HI educational programs need to work on linking their program objectives with a Saudi Health Informatics Career Framework (SHICF) and labor market needs. Ignoring such an important issue may result in unemployed Saudi HI graduates or HI graduates working in related fields other than HI.
From public to mixed ownership in local public services provision: an empirical analysis

ABSTRACT There is a long tradition of companies that provide local public services, such as energy distribution or solid waste collection, being strategically important for the promotion of the development of areas where they are present and having a great influence on citizens’ quality of life. This article examines the determinants of the choice of ownership structure for Italian companies that provide local public services, and the effects that this choice has on their performance. Economic and financial data at company level was merged with economic, political, financial and territorial data on the municipality with the majority of shares in it. A two-stage multinomial selection model was employed, in order to carry out the analysis with more than two alternative ownership structures and to control for endogeneity. The empirical evidence indicates that the municipality’s political and budgetary conditions matter in the choice of ownership structure. Although the computed Average Treatment Effects seem to indicate that mixed ownership increases operating efficiency, the profitability indicators provide evidence to the contrary.
Stimulation of AT2 receptor exerts beneficial effects in stroke-prone rats: focus on renal damage

Background and aim Angiotensin II acts through two major receptors: AT1-R and AT2-R. It is known that the stimulation of AT1-R mediates vasoconstriction, cell proliferation and fibrosis, aldosterone release and inflammatory response but, although the stimulation of AT2-R is thought to promote vasodilation and anti-inflammatory effects, its real in-vivo functions are still unclear. The aim of this study was to investigate the effects of specific and selective AT2-R stimulation on the pathological events occurring in spontaneously hypertensive stroke-prone rats (SHRSPs). Methods and results SHRSPs who were fed a high-salt diet underwent long-term treatment with vehicle or compound 21 (C21), a nonpeptide selective AT2-R agonist, at doses of 0.75, 5 and 10 mg/kg per day. The vehicle-treated rats developed brain abnormalities detectable by magnetic resonance imaging after 42.5 ± 7.5 days, and died 43 ± 9.5 days after the start of the dietary treatment. The highest C21 dose delayed the occurrence of brain damage (P < 0.001 vs. vehicle-treated SHRSPs) and prolonged survival (P < 0.001) without affecting blood pressure. These beneficial effects of C21 were abolished by the administration of PD123319, an AT2-R antagonist. C21 treatment preserved renal structure by preventing inflammatory cell infiltration, collagen accumulation, and the neo-expression of vimentin; it also prevented the increased plasma renin activity and accumulation of urinary acute-phase proteins observed in the vehicle-treated rats. Conclusion Specific and selective AT2-R stimulation has beneficial effects on the pathological events occurring in SHRSPs. These data indicate a new avenue for the pharmacological treatment of diseases in which modulation of the renin–angiotensin system is required.
Diagnostic arthroscopy and longitudinal open lateral release

The purpose of this study was as follows: 1) to review our previous findings regarding surgical outcome fol lowing open retinacular release but now at a mean followup of 4 years, 2) to test the validity of the correc tion of patellar "overhang" by Merchant views at 4 years and correlate this with outcome, 3) to correlate arthros copic findings of lateral overhang, patellofemoral carti lage disease, preoperative Q-angle measurements, and duration of symptoms with outcome at 4 years postre lease. The surgical technique of diagnostic arthroscopy and open longitudinal release has been described pre viously by the author, emphasizing the specific anatom ical structures to be divided. The synovium was never incised and the retinacular structures were freed to allow reduction of the patella medially. Sixty patients comprising 76 knees were reviewed at a mean followup of 4 years postrelease. Followup included evaluation of Merchant views and Q angles, physical examination, and determination of patient satisfaction. Eighty-five percent of the patients followed retained the good to excellent ratings they had at the 2 year followup. "Re duction" of the released patella on Merchant views correlated well with surgical outcome and patient sat isfaction in 95% of cases. Residual Merchant view patellar tilt or excessive lateral position correlated well with poor results. Hematoma formation was the leading cause of failure. A severe preoperative Q angle corre lated somewhat with results at 4 years but this was not statistically significant. The degree of articular cartilage disease at prerelease arthroscopy did not correlate at all with results at 4 years, nor did the duration of preoperative symptoms. "Good outcome" preoperative findings included biomechanical peripatellar pain, a pos itive patellar restriction/apprehension test, and a posi tive Merchant view. Intraoperative "good outcome" pre operative findings included a positive arthroscopic ov erhang sign, evidence of patellar maltracking, and an abnormal toughened lateral retinaculum. "Reduction" of the released patella on quadriceps films taken 6 weeks after surgery and rehabilitation remained un changed at 4 years, correlating exceedingly well with excellent clinical results.
The Cytoplasmic Domains of a β1 Integrin Mediate Polarization in Madin-Darby Canine Kidney Cells by Selective Basolateral Stabilization*

In Madin-Darby canine kidney cells, newly synthesized apical and basolateral membrane proteins are generally transported directly to their respective cell surface domain due to targeting determinants that mediate sorting in the Golgi complex. In several basolateral membrane proteins, these targeting determinants reside in the cytoplasmic domains. We show here that basolateral expression of the human α5β1 integrin in stably transfected Madin-Darby canine kidney cells is also mediated by the cytoplasmic domains. Distinct regions in both cytoplasmic domains were found to be sufficient to mediate basolateral expression independently from one another. Unexpectedly, newly synthesized wild-type α5β1 and basolaterally expressed chimeras containing the cytoplasmic domain of either α5or β1 were integrated into both cell surface domains, preferentially apically, during biosynthesis. The apical pools of wild-type integrin and chimeric subunits were found to become quickly degraded, whereas the basolateral pools were stabilized. Thus, the cytoplasmic domains of the α5β1 integrin are independently sufficient to mediate sorting by selective basolateral stabilization.
Synthesis, characterization, and some immunological properties of conjugates composed of the detoxified lipopolysaccharide of Vibrio cholerae O1 serotype Inaba bound to cholera toxin

Protection against cholera has been correlated with the level of serum vibriocidal antibodies. The specificity of these vibriocidal antibodies was mostly to the lipopolysaccharide (LPS). We synthesized conjugates of detoxified LPS with cholera toxin (CT) and other proteins in order to elicit serum LPS antibodies with vibriocidal activity. Treatment with hydrazine (deacylated LPS) reduced the endotoxic properties of the LPS to clinically acceptable levels and resulted in a molecule larger and more antigenic than the saccharide produced by acid hydrolysis. More immunogenic conjugates resulted from multipoint compared with single-point attachment of the deacylated LPS to the protein. The conjugates containing CT had low levels of pyrogen and no toxic activity upon Chinese hamster ovary cells and elicited booster responses of vibriocidal and CT antibodies when injected subcutaneously as saline solutions into mice; the vibriocidal titers were similar to those elicited by comparable doses of cellular vaccines. We suggest how serum vibriocidal antibodies might prevent cholera.
Population-based study of first onset and chronicity in major depressive disorder.

CONTEXT There are no studies of the natural history of major depressive disorder that lack prevalence and clinic biases. OBJECTIVES To estimate risk factors for first lifetime onset and parameters of chronicity following the first episode, including duration, recovery, and recurrence, and to search for predictors of each parameter. DESIGN Prospective population-based cohort study with 23 years of follow-up. SETTING East Baltimore, Maryland, an urban setting. PARTICIPANTS Probability sample of 3481 adult household residents in 1981, including 92 with first lifetime onset of major depressive disorder during the course of the follow-up, and 1739 other participants followed up for at least 13 years. OUTCOME MEASURES Diagnostic Interview Schedule and Life Chart Interview. RESULTS Female participants showed higher risk of onset of disorder, longer duration of episodes, and a nonsignificant tendency for higher risk of recurrence. Sex was not related to recovery. The median episode length was 12 weeks. About 15% of 92 individuals with first episodes did not have a year free of episodes, even after 23 years. About 50% of first episode participants recovered and had no future episodes. The evolution of the course was relatively stable from first to later episodes. Individuals with 1 or 2 short alleles of the serotonin transporter gene were at higher risk for an initial episode, but experienced episodes of shorter duration. There were few strong predictors of recovery or recurrence. CONCLUSIONS Major depressive disorder is unremitting in 15% of cases and recurrent in 35%. About half of those with a first-onset episode recover and have no further episodes.
International Comparison of Age Discrimination Laws

European age discrimination legislation is discussed in the context of the U.S. Age Discrimination in Employment Act (ADEA) and related state laws. U.S. law was originally introduced to protect productive older workers from age stereotypes, but more recently preventing age discrimination has become important as a means of keeping costs down on entitlement programs as the population ages. Changes in enforcement, penalties, exemptions, length of time to file, and burden of proof have changed the effects of the laws over time. The ADEA has had both positive effects on currently employed older workers and negative effects on the hiring of older workers. Enforcement and publicity are offered as possible explanations for the strength of these positive and negative effects. Age discrimination legislation in Europe, indicated in the Framework Directive 2000/78, is driven by economic and political considerations. European legislation calls for less enforcement and more exemptions than the corresponding U.S. cases that could lead to smaller effects on employment. However, pensions, disability, unemployment, and social security potentially have a stronger effect on social norms for retirement age than does anti-discrimination legislation.
Group interpersonal psychotherapy for low-income women with posttraumatic stress disorder

Abstract The aim of this study was to assess the efficacy of group interpersonal psychotherapy (IPT) for low-income women with chronic posttraumatic stress disorder (PTSD) subsequent to interpersonal trauma. Non-treatment-seeking predominantly minority women were recruited in family planning and gynecology clinics. Individuals with interpersonal trauma histories (e.g., assault, abuse, and molestation) who met criteria for current PTSD (N=48) were randomly assigned to treatment or a wait list. Assessments were conducted at baseline, treatment termination, and 4-month follow-up; data analysis used a mixed-effects regression approach with an intent-to-treat sample. The results showed that IPT was significantly more effective than the wait list in reducing PTSD and depression symptom severity. IPT participants also had significantly lower scores than waitlist individuals on four interpersonal functioning subscales: Interpersonal Sensitivity, Need for Social Approval, Lack of Sociability, and Interpersonal Ambivalence.
Killing of Normal Melanocytes, Combined with Heat Shock Protein 70 and CD40L Expression, Cures Large Established Melanomas

Previously, we showed that nine intradermal injections of a plasmid in which the HSVtk suicide gene is expressed from a melanocyte-specific promoter (Tyr-HSVtk), combined with a plasmid expressing heat shock protein 70 (CMV-hsp70), along with systemic ganciclovir, kills normal melanocytes and raises a CD8+ T cell response that is potent enough to eradicate small, 3-day established B16 tumors. We show in this study that, in that regimen, hsp70 acts as a potent immune adjuvant through TLR-4 signaling and local induction of TNF-α. hsp70 is required for migration of APC resident in the skin to the draining lymph nodes to present Ags, derived from the killing of normal melanocytes, to naive T cells. The addition of a plasmid expressing CD40L increased therapeutic efficacy, such that only six plasmid injections were now required to cure large, 9-day established tumors. Generation of potent immunological memory against rechallenge in cured mice accompanied these therapeutic gains, as did induction of aggressive autoimmune symptoms. Expression of CD40L, along with hsp70, increased both the frequency and activity of T cells activated against melanocyte-derived Ags. In this way, addition of CD40L to the hsp70-induced inflammatory killing of melanocytes can be used to cure large established tumors and to confer immunological memory against tumor cells, although a concomitant increase in autoimmune sequelae also is produced.
Spectacular Rhetorics

Spectacular Rhetorics is a rigorous analysis of the rhetorical frameworks and narratives that underlie human rights law, shape the process of cultural and legal recognition, and delimit public responses to violence and injustice. Integrating visual and textual criticism, Wendy S. Hesford scrutinizes “spectacular rhetoric,” the use of visual images and rhetoric to construct certain bodies, populations, and nations as victims and incorporate them into human rights discourses geared toward Westerners, chiefly Americans. Hesford presents a series of case studies critiquing the visual representations of human suffering in documentary films, photography, and theater. In each study, she analyzes works addressing a prominent contemporary human rights cause, such as torture and unlawful detention, ethnic genocide and rape as a means of warfare, migration and the trafficking of women and children, the global sex trade, and child labor. Through these studies, she demonstrates how spectacular rhetoric activates certain cultural and national narratives and social and political relations, consolidates identities through the politics of recognition, and configures material relations of power and difference to produce and, ultimately, to govern human rights subjects.
Block of potassium currents in rat isolated sympathetic neurones by tricyclic antidepressants and structurally related compounds

1 The block of K+ currents by the tricyclic antidepressants (TCAs), imipramine and amitriptyline and three structurally related compounds, chlorpromazine, tacrine and carbamazepine was investigated in rat isolated sympathetic neurones by whole‐cell voltage‐clamp recording. 2 At a concentration of 10 μm, imipramine, amitriptyline and chlorpromazine all blocked the delayed rectifier K+ current (IKv) by about the same extent, 54%, 47% and 53%. Tacrine was less effective (10%) while carbamazepine was ineffective at all concentrations tested. 3 The degree of block by the four effective compounds was relatively independent of the size of the voltage‐step. Neither the activation nor the inactivation rates of IKv were altered by the blocking drugs. 4 Concentration‐response relationships for imipramine and tacrine showed that imipramine was about 7 fold more potent than tacrine but that the maximum inhibition and the Hill slope were the same for both compounds. 5 Amitriptyline, chlorpromazine and imipramine (at 10 μm) were 2–3 fold more potent at inhibiting the sustained K+ current (mostly IKv) than the transient K+ current (mostly IA). Tacrine, however, was equally effective in blocking both components.
Hypoxic Preconditioning Augments Efficacy of Human Endothelial Progenitor Cells for Therapeutic Neovascularization

A subset of human peripheral blood mononuclear cells (PB-MNCs) differentiate into endothelial progenitor cells (EPCs) that participate in postnatal neovascularization. Although tissue ischemia can mobilize EPCs from bone marrow, the effects of hypoxia on differentiation and angiogenic function of EPCs are little known. We examined whether hypoxic conditioning would modulate differentiation and function of human PB-MNC-derived EPCs. A subset of PB-MNCs gave rise to EPC-like attaching (AT) cells under either normoxic or hypoxic conditions. However, hypoxia much enhanced the differentiation of AT cells from PB-MNCs compared with normoxia. AT cells released vascular endothelial growth factor (VEGF) protein and expressed CD31 and kinase insert domain receptor/VEGFR-2, endothelial lineage markers, on their surface, which were also enhanced by hypoxia. Both a neutralizing anti-VEGF mAb and a KDR-specific receptor tyrosine kinase inhibitor, SU1498, suppressed PB-MNC differentiation into EPC-like AT cells in a dose-dependent manner. Migration of AT cells in response to VEGF as examined by a modified Boyden chamber apparatus was also enhanced by hypoxia. Finally, in vivo neovascularization efficacy was significantly enhanced by in vitro hypoxic conditioning of AT cells when cells were transplanted into the ischemic hindlimb of immunodeficient nude rats. In conclusion, hypoxia directly stimulated differentiation of EPC-like AT cells from human PB-MNC culture. Moreover, hypoxic preconditioning of AT cells before in vivo transplantation is a useful means to enhance therapeutic vasculogenesis.