A therapeutic target for CKD: activin A facilitates TGFß1 profibrotic signaling.

BACKGROUND: TGFß1 is a major profibrotic mediator in chronic kidney disease (CKD). Its direct inhibition, however, is limited by adverse effects. Inhibition of activins, also members of the TGFß superfamily, blocks TGFß1 profibrotic effects, but the mechanism underlying this and the specific activin(s) involved are unknown. METHODS: Cells were treated with TGFß1 or activins A/B. Activins were inhibited generally with follistatin, or specifically with neutralizing antibodies or type I receptor downregulation. Cytokine levels, signaling and profibrotic responses were assessed with ELISA, immunofluorescence, immunoblotting and promoter luciferase reporters. Wild-type or TGFß1-overexpressing mice with unilateral ureteral obstruction (UUO) were treated with an activin A neutralizing antibody. RESULTS: In primary mesangial cells, TGFß1 induces secretion primarily of activin A, which enables longer-term profibrotic effects by enhancing Smad3 phosphorylation and transcriptional activity. This results from lack of cell refractoriness to activin A, unlike that for TGFß1, and promotion of TGFß type II receptor expression. Activin A also supports transcription through regulating non-canonical MRTF-A activation. TGFß1 additionally induces secretion of activin A, but not B, from tubular cells, and activin A neutralization prevents the TGFß1 profibrotic response in renal fibroblasts. Fibrosis induced by UUO is inhibited by activin A neutralization in wild-type mice. Worsened fibrosis in TGFß1-overexpressing mice is associated with increased renal activin A expression and is inhibited to wild-type levels with activin A neutralization. CONCLUSIONS: Activin A facilitates TGFß1 profibrotic effects through regulation of both canonical (Smad3) and non-canonical (MRTF-A) signaling, suggesting it may be a novel therapeutic target for preventing fibrosis in CKD.

Barriers and facilitators of implementing electronic monitors to improve adherence and health outcomes in tuberculosis patients: protocol for a systematic review based on the Consolidated Framework for Implementation Research.

BACKGROUND: Tuberculosis (TB) has been regarded as 'a relentless scourge', increasing morbidity and mortality and burdening vulnerable populations. Poor adherence to TB treatment and ineffective traditional interventions hinders TB control. A novel TB approach called 'electronic monitors', equipping medication boxes with daily audio or visual reminders for electronically monitoring medication intake, seems promising in improving adherence and health outcomes and overcoming the weaknesses of traditional interventions. However, no review has systematically examined and synthesized the influencing factors of implementing electronic monitors. Implementation research offers the means to analyse the influencing factors of the implementation and its process, fitting well with the aim of this review. Therefore, the widely recognized Consolidated Framework for Implementation Research (CFIR), which offers a common taxonomy for evaluating intervention implementation, will be adopted to systematically identify barriers and facilitators of the electronic monitors for improving adherence and health outcomes in patients with TB. METHODS AND ANALYSIS: The systematic review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature research will be conducted in five electronic databases (Ovid MEDLINE, CINAHL, EMBASE, Cochrane Library and Web of Science) to identify the barriers and facilitators of implementing electronic monitors in patients with TB. The CFIR will be used as a guide for categorizing and synthesizing the barriers and facilitators. Study screening, data extraction, quality appraisal and data analysis will be conducted by two independent reviewers. The use of additional reviewers will solve any disagreements between the two reviewers. DISCUSSION: Given the increased prominence of TB epidemiology and the adherence problem of electronic monitors, there is a solid rationale for synthesizing the existing studies via the CFIR. The findings and conclusion of this review will lay bare the achievements and effectiveness of implementing electronic monitors, as well as the attendant gaps and limitations. Further strategies for facilitating the implementation of electronic monitors will also be explored. This review will be of essential significance for research and practice, supporting future academic research initiatives centred on patients with TB and aiding electronic monitor design in lowering the morbidity and mortality associated with TB disease. TRIAL REGISTRATION NUMBER: PROSPERO: CRD42023395747.

The epidemiologic impact and cost-effectiveness of new tuberculosis vaccines on multidrug-resistant tuberculosis in India and China.

BACKGROUND: Despite recent advances through the development pipeline, how novel tuberculosis (TB) vaccines might affect rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is unknown. We investigated the epidemiologic impact, cost-effectiveness, and budget impact of hypothetical novel prophylactic prevention of disease TB vaccines on RR/MDR-TB in China and India. METHODS: We constructed a deterministic, compartmental, age-, drug-resistance- and treatment history-stratified dynamic transmission model of tuberculosis. We introduced novel vaccines from 2027, with post- (PSI) or both pre- and post-infection (P&PI) efficacy, conferring 10 years of protection, with 50% efficacy. We measured vaccine cost-effectiveness over 2027-2050 as USD/DALY averted-against 1-times GDP/capita, and two healthcare opportunity cost-based (HCOC), thresholds. We carried out scenario analyses. RESULTS: By 2050, the P&PI vaccine reduced RR/MDR-TB incidence rate by 71% (UI: 69-72) and 72% (UI: 70-74), and the PSI vaccine by 31% (UI: 30-32) and 44% (UI: 42-47) in China and India, respectively. In India, we found both USD 10 P&PI and PSI vaccines cost-effective at the 1-times GDP and upper HCOC thresholds and P&PI vaccines cost-effective at the lower HCOC threshold. In China, both vaccines were cost-effective at the 1-times GDP threshold. P&PI vaccine remained cost-effective at the lower HCOC threshold with 49% probability and PSI vaccines at the upper HCOC threshold with 21% probability. The P&PI vaccine was predicted to avert 0.9 million (UI: 0.8-1.1) and 1.1 million (UI: 0.9-1.4) second-line therapy regimens in China and India between 2027 and 2050, respectively. CONCLUSIONS: Novel TB vaccination is likely to substantially reduce the future burden of RR/MDR-TB, while averting the need for second-line therapy. Vaccination may be cost-effective depending on vaccine characteristics and setting.

Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in normal physiology, ROCK inhibition has been found to be effective in attenuating DKD in preclinical models. However, this has not been evaluated in clinical studies as of yet. Alternate means of inhibiting RhoA/ROCK signaling involve the identification of disease-specific activators. This report presents evidence showing the activation of RhoA/ROCK signaling both in vitro in glomerular mesangial cells and in vivo in diabetic kidneys by two recently described novel pathogenic mediators of fibrosis in DKD, activins and cell-surface GRP78. Neither are present in normal kidneys. Activin inhibition with follistatin and neutralization of cell-surface GRP78 using a specific antibody blocked RhoA activation in mesangial cells and in diabetic kidneys. These data identify two novel RhoA/ROCK activators in diabetic kidneys that can be evaluated for their efficacy in inhibiting the progression of DKD.

Cell surface expression of 78-kDa glucose-regulated protein (GRP78) mediates diabetic nephropathy.

The 78-kDa glucose-regulated protein (GRP78) is a well-established endoplasmic reticulum (ER)-resident chaperone that maintains protein homeostasis and regulates the unfolded protein response. Under conditions of ER stress, GRP78 is also expressed at the cell surface and implicated in tumorigenesis, immunity, and cellular signaling events. The role of cell surface-associated GRP78 (csGRP78) in the pathogenesis of diabetic nephropathy has not yet been defined. Here we explored the role of csGRP78 in regulating high glucose (HG)-induced profibrotic AKT Ser/Thr kinase (AKT) signaling and up-regulation of extracellular matrix proteins. Using primary kidney mesangial cells, we show that HG treatment, but not the osmotic control mannitol, induces csGRP78 expression through an ER stress-dependent mechanism. We found that csGRP78, known to be located on the outer membrane leaflet, interacts with the transmembrane protein integrin ß1 and activates focal adhesion kinase and downstream PI3K/AKT signaling. Localization of GRP78 at the cell surface and its interaction with integrin ß1 were also required for extracellular matrix protein synthesis in response to HG. Surprisingly, both the N and C termini of csGRP78 were necessary for this profibrotic response. Increased localization of GRP78 at the plasma membrane was also found in the glomerular mesangial area of type 1 diabetic mice in two different models (streptozotocin-induced and Akita). In freshly isolated glomeruli from Akita mice, csGRP78 co-localized with the mesangial cell surface marker α8-integrin. In conclusion, our work reveals a role for csGRP78 in HG-induced profibrotic responses in mesangial cells, informing a potential approach to treating diabetic nephropathy.

Regulation of profibrotic responses by ADAM17 activation in high glucose requires its C-terminus and FAK.

Glomerular matrix accumulation is the hallmark of diabetic nephropathy. The metalloprotease ADAM17 mediates high glucose (HG)-induced matrix production by kidney mesangial cells through release of ligands for the epidermal growth factor receptor. Here, we study the mechanism by which HG activates ADAM17. We find that the C-terminus is essential for ADAM17 activation and the profibrotic response to HG. In the C-terminus, Src-mediated Y702 phosphorylation and PI3K-MEK-Erk-mediated T735 phosphorylation are crucial for ADAM17 activation, both are also required for the HG-induced increase in cell surface mature ADAM17. The non-receptor tyrosine kinase FAK is a central mediator of these processes. These data not only support a crucial role for the C-terminus in ADAM17 activation and downstream profibrotic responses to HG, but also highlight FAK as a potential alternative therapeutic target for diabetic nephropathy.

The caveolin-1 regulated protein follistatin protects against diabetic kidney disease.

Glomerular matrix protein accumulation, mediated largely by mesangial cells, is central to the pathogenesis of diabetic kidney disease. Our previous studies showed that the membrane microdomains caveolae and their marker protein caveolin-1 regulate matrix protein synthesis in mesangial cells in response to diabetogenic stimuli, and that caveolin-1 knockout mice are protected against diabetic kidney disease. In a screen to identify the molecular mechanism underlying this protection, we also established that secreted antifibrotic glycoprotein follistatin is significantly upregulated by caveolin-1 deletion. Follistatin potently neutralizes activins, members of the transforming growth factor-ß superfamily. A role for activins in diabetic kidney disease has not yet been established. Therefore, in vitro, we confirmed the regulation of follistatin by caveolin-1 in primary mesangial cells and showed that follistatin controls both basal and glucose-induced matrix production through activin inhibition. In vivo, we found activin A upregulation by immunohistochemistry in both mouse and human diabetic kidney disease. Importantly, administration of follistatin to type 1 diabetic Akita mice attenuated early diabetic kidney disease, characterized by albuminuria, hyperfiltration, basement membrane thickening, loss of endothelial glycocalyx and podocyte nephrin, and glomerular matrix accumulation. Thus, activin A is an important mediator of high glucose-induced profibrotic responses in mesangial cells, and follistatin may be a potential novel therapy for the prevention of diabetic kidney disease.

Caveolin-1 regulation of Sp1 controls production of the antifibrotic protein follistatin in kidney mesangial cells.

BACKGROUND: We previously showed that caveolin-1 (cav-1), an integral membrane protein, is required for the synthesis of matrix proteins by glomerular mesangial cells (MC). In a previous study to understand how cav-1 is involved in regulating matrix production, we had identified significant upregulation of the antifibrotic protein follistatin in cav-1 knockout MC. Follistatin inhibits the profibrotic effects of several members of the transforming growth factor beta superfamily, in particular the activins. Here, we characterize the molecular mechanism through which cav-1 regulates the expression of follistatin. METHODS: Kidneys from cav-1 wild type and knockout (KO) mice were analyzed and primary cultures of MC from cav-1 wild-type and KO mice were utilized. FST promoter deletion constructs were generated to determine the region of the promoter important for mediating FST upregulation in cav-1 KO MC. siRNA-mediated down-regulation and overexpression of Sp1 in conjunction with luciferase activity assays, immunoprecipitation, western blotting and ChiP was used to assess the role of Sp1 in transcriptionally regulating FST expression. Pharmacologic kinase inhibitors and specific siRNA were used to determine the post-translational mechanism through which cav-1 affects Sp1 activity. RESULTS: Our results establish that follistatin upregulation occurs at the transcript level. We identified Sp1 as the critical transcription factor regulating activation of the FST promoter in cav-1 KO MC through binding to a region within 123 bp of the transcription start site. We further determined that the lack of cav-1 increases Sp1 nuclear levels and transcriptional activity. This occurred through increased phosphoinositide 3-kinase (PI3K) activity and downstream protein kinase C (PKC) zeta-mediated phosphorylation and activation of Sp1. CONCLUSIONS: These findings shed light on the transcriptional mechanism by which cav-1 represses the expression of a major antifibrotic protein, and can inform the development of novel antifibrotic treatment strategies.

Photoelectron spectroscopy of [Mo6X14]2- dianions (X = Cl-I).

Photoelectron spectroscopy and theoretical investigations have been performed to systematically probe the intrinsic electronic properties of [Mo6X14]2- (X = halogen). All three PE spectra of gaseous [Mo6X14]2- (X = Cl, Br, I) dianions, which were generated by electrospray ionization, exhibit multiple resolved peaks in the recorded binding energy range. Theoretical investigations on the orbital structure and charge distribution were performed to support interpretation of the observed spectra and were further extended onto [Mo6F14]2-, a dianion that was not available for the experimental study. The measured adiabatic (ADE) and vertical detachment energies (VDE) for X = Cl-I were well reproduced by density functional theory calculations (accuracy ∼0.1 eV). Corresponding ADE/VDE values for the dianions were found to be 1.48/2.13 (calc.) and 2.30/2.65, 2.30/2.62, and 2.20/2.42 eV (all expt.) for X = F, Cl, Br, and I, respectively, showing an interesting buckled trend of electron binding energy (EBE) along the halogen series, i.e., EBE (F) ≪ EBE (Cl) ∼ EBE (Br) > EBE (I). Molecular orbital analyses indicate different mixing of metal and halogen atomic orbitals, which is strongly dependent on the nature of X, and suggest that the most loosely bound electrons are detached mainly from the metal core for X = F and Cl, but from halide ligands for X = Br and I. The repulsive Coulomb barrier (RCB), estimated from the photon energy dependent spectra, decreases with increasing halogen size, from 1.8 eV for X = Cl to 1.6 eV for X = I. Electrostatic potential modeling confirms the experimental RCB values and predicts that the most favorable electron detaching pathway should lie via the face-bridging halide ligands.

Photoelectron spectroscopy of solvated dicarboxylate and alkali metal ion clusters, M+[O2C(CH2)2CO2]2- [H2O]n (M = Na, K; n = 1-6).

We present results of combined experimental photoelectron spectroscopy and theoretical modeling studies of solvated dicarboxylate species (-O2C(CH2)2CO2-) in complex with Na+ and K+ metal cations. These ternary clusters serve as simple models for the investigation of aqueous ion/solute specific effects that play an important role in biological systems. The experimental characterization of these systems was performed in the presence of up to six solvating waters. In both Na+ and K+ cases, we observe the presence of one major broad band that gradually shifts to higher electron binding energy (EBE) with an increasing number of waters. In the Na+ case further detailed analysis of experimental spectra was performed using ab initio calculations. In particular, we have identified the structures of the lowest energy clusters whose EBE values match well the major band in the experimental spectra. Our results show that evolution of an aqueous solvation shell emphasizes the coordination of the negatively charged carboxylate groups accompanied by simultaneous interaction with metal cations. Calculations also indicate that in the solvation range investigated experimentally (up to 6 waters), Na+ retains direct contact with the dicarboxylate species, i.e. a contact ion-pair (CIP) complex. Preliminary modeling studies show evidence of an alternative solvent separated ion-pair complex once the solvation range approaches 8 waters, however its energy still remains above that of (∼7-8 kcal/ mol-1) the CIP complex. At a higher number of waters (n = 3 for Na+ and n = 5 for K+), the experimental spectra also show the development of a weak low energy band. Its origin cannot be precisely identified. Our calculations in the Na+ case point out the existence of a quaternary complex consisting of Na+, H2O, OH- and a singly protonated dicarboxylate anion (HO2C(CH)2CO2-). Such a complex appears to be stabilized in the solvation range corresponding to the appearance of the low EBE band and does match its peak, even though the energy of such a complex is fairly high compared to the ternary structure.

Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate.

As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors--atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)--occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.

High Glucose Up-regulates ADAM17 through HIF-1α in Mesangial Cells.

We previously showed that ADAM17 mediates high glucose-induced matrix production by kidney mesangial cells. ADAM17 expression is increased in diabetic kidneys, suggesting that its up-regulation may augment high glucose profibrotic responses. We thus studied the effects of high glucose on ADAM17 gene regulation. Primary rat mesangial cells were treated with high glucose (30 mm) or mannitol as osmotic control. High glucose dose-dependently increased ADAM17 promoter activity, transcript, and protein levels. This correlated with augmented ADAM17 activity after 24 h versus 1 h of high glucose. We tested involvement of transcription factors shown in other settings to regulate ADAM17 transcription. Promoter activation was not affected by NF-κB or Sp1 inhibitors, but was blocked by hypoxia-inducible factor-1α (HIF-1α) inhibition or down-regulation. This also prevented ADAM17 transcript and protein increases. HIF-1α activation by high glucose was shown by its increased nuclear translocation and activation of the HIF-responsive hypoxia-response element (HRE)-luciferase reporter construct. Assessment of ADAM17 promoter deletion constructs coupled with mutation analysis and ChIP studies identified HIF-1α binding to its consensus element at -607 as critical for the high glucose response. Finally, inhibitors of epidermal growth factor receptor (EGFR) and downstream PI3K/Akt, or ADAM17 itself, prevented high glucose-induced HIF-1α activation and ADAM17 up-regulation. Thus, high glucose induces ADAM17 transcriptional up-regulation in mesangial cells, which is associated with augmentation of its activity. This is mediated by HIF-1α and requires EGFR/ADAM17 signaling, demonstrating the potentiation by ADAM17 of its own up-regulation. ADAM17 inhibition thus provides a potential novel therapeutic strategy for the treatment of diabetic nephropathy.

Initial hydration behavior of sodium iodide dimer: photoelectron spectroscopy and ab initio calculations.

We investigated (NaI)2(-)(H2O)n (n = 0-6) clusters to examine the initial solvation process of (NaI)2 in water, using negative ion photoelectron spectroscopy and theoretical calculations. The structures of these clusters and their neutrals were determined by comparing ab initio calculations with experimental results. It is found that bare (NaI)2(-) is a L-shaped structure and the corresponding neutral is a rhombus. In (NaI)2(-)(H2O), the water molecule prefers to interact with the middle Na atom of the L-shaped (NaI)2(-). For (NaI)2(-)(H2O)n clusters with n = 2-3, two types of structures are nearly degenerate in energy: one is L-shaped and the other is pyramid-shaped. As for (NaI)2(-)(H2O)n with n = 4-6, the dominant structures are pyramid-shaped. For the anionic clusters, one of the Na-I distances increases abruptly when n = 2; for the neutral clusters, rapid lengthening of the Na-I distances occurs when n = 4. Additionally, analyses of the reduced density gradient were carried out, and the results reveal that Na(+)-water interactions dominate in (NaI)2(-)(H2O)n for n≤ 4, whereas I(-)-water and water-water interactions are significantly enhanced when n increases to 5.

Anomalous properties and the liquid-liquid phase transition in gallium.

A group of materials including water and silicon exhibit many anomalous behaviors, e.g., density anomaly and diffusivity anomaly (increase upon compression). These materials are hypothesized to have a liquid-liquid phase transition (LLPT) and the critical fluctuation in the vicinity of the liquid-liquid critical point is considered as the origin of different anomalies. Liquid gallium was also reported to have a LLPT, yet whether it shows similar water-like anomalies is not yet studied. Using molecular dynamics simulations on a modified embedded-atom model, we study the thermodynamic, dynamic, and structural properties of liquid gallium as well as its LLPT. We find that, similar to water-like materials predicted to have the LLPT, gallium also shows different anomalous behaviors (e.g., density anomaly, diffusivity anomaly, and structural anomaly). We also find that its thermodynamic and structural response functions are continuous and show maxima in the supercritical region, the loci of which asymptotically approach to the other and merge to the Widom line. These phenomena are consistent with the supercritical phenomenon in a category of materials with a liquid-liquid critical point, which could be common features in most materials with a LLPT.

Hydration of potassium iodide dimer studied by photoelectron spectroscopy and ab initio calculations.

We measured the photoelectron spectra of (KI)2-(H2O)n (n = 0-3) and conducted ab initio calculations on (KI)2-(H2O)n anions and their corresponding neutrals up to n = 6. Two types of spectral features are observed in the experimental spectra of (KI)2-(H2O) and (KI)2-(H2O)2, indicating that two types of isomers coexist, in which the high EBE feature corresponds to the hydrated chain-like (KI)2- while the low EBE feature corresponds to the hydrated pyramidal (KI)2-. In (KI)2-(H2O)3, the (KI)2- unit prefers a pyramidal configuration, and one of the K-I distances is elongated significantly, thus a K atom is firstly separated out from the (KI)2- unit. As for the neutrals, the bare (KI)2 has a rhombus structure, and the structures of (KI)2(H2O)n are evolved from the rhombus (KI)2 unit by the addition of H2O. When the number of water molecules reaches 4, the K-I distances have significant increment and one of the I atoms prefers to leave the (KI)2 unit. The comparison of (KI)2(H2O)n and (NaI)2(H2O)n indicates that it is slightly more difficult to pry apart (KI)2 than (NaI)2 via hydration, which is in agreement with the lower solubility of KI compared to that of NaI.

SREBP-1 Mediates Angiotensin II-Induced TGF-ß1 Upregulation and Glomerular Fibrosis.

Angiotensin II is an important mediator of CKD of diverse etiology. A common pathologic feature of CKD is glomerular fibrosis, a central mediator of which is the profibrotic cytokine TGF-ß. The mechanisms underlying the induction of TGF-ß and matrix by angiotensin II are not completely understood. Recent studies showed that overexpression of the transcription factor SREBP-1 induces glomerular sclerosis and that angiotensin II can activate SREBP-1 in tubular cells. We thus studied whether SREBP-1 is activated by angiotensin II and mediates angiotensin II-induced profibrogenic responses in primary rat mesangial cells. Treatment of cells with angiotensin II induced the upregulation and activation of SREBP-1. Angiotensin II-induced activation of SREBP-1 required signaling through the angiotensin II type I receptor and activation of PI3K/Akt in addition to the chaperone SCAP and protease S1P. Notably, angiotensin II-induced endoplasmic reticulum stress was identified as a key mediator of Akt-SREBP-1 activation, and inhibition of endoplasmic reticulum stress or SREBP-1 prevented angiotensin II-induced SREBP-1 binding to the TGF-ß promoter, TGF-ß upregulation, and downstream fibronectin upregulation. Endoplasmic reticulum stress alone, however, did not induce TGF-ß upregulation despite activating SREBP-1. Although not required for SREBP-1 activation by angiotensin II, EGF receptor signaling was necessary for activation of the SREBP-1 cotranscription factor Sp1, which provided a required second signal for TGF-ß upregulation. In vivo, endoplasmic reticulum stress and SREBP-1-dependent effects were induced in glomeruli of angiotensin II-infused mice, and administration of the SREBP inhibitor fatostatin prevented angiotensin II-induced TGF-ß upregulation and matrix accumulation. SREBP-1 and endoplasmic reticulum stress thus provide potential novel therapeutic targets for the treatment of CKD.

Effective reimbursement rates of the rural health insurance among uncomplicated tuberculosis patients in China.

OBJECTIVE: China has established universal health coverage for 830 million rural residents through the rapid expansion of the New Cooperative Medical Scheme (NCMS). This study accesses the effective reimbursement rates of NCMS among patients with tuberculosis (TB) who lived in counties where their schemes covered costs within TB dispensaries and those who did not. METHODS: We randomly selected 50 patients with uncomplicated TB from each of the eight counties in two provinces. We reviewed all patient clinical charts and conducted face-to-face surveys. Effective reimbursement was measured as the proportion of patients who received reimbursement from NCMS and the average reimbursement rate of total medical costs. RESULTS: A total of 393 patients with TB were included with 186 from Zhejiang and 206 from Sichuan. In the covered group, only 41% of patients with TB received reimbursements for medical costs in TB dispensary in Zhejiang as compared to 84% in Sichuan, because patients in Zhejiang needed to keep their bills and claim later, while Sichuan had patient medical costs automatically deducted at the point of care. Patients in the covered group had a significantly higher average reimbursement rate compared with those in the uncovered group (13% vs. 8% in Zhejiang and 17% vs. 12% in Sichuan). For all patients, the biggest cost was due to hospitalisation, and their overall reimbursement rates were low. CONCLUSION: New Cooperative Medical Scheme has not relieved the financial burden of TB-related medical costs. NCMS should cover costs in TB dispensaries. Measures are also needed to minimise unnecessary hospitalisation, and lower the barriers to claims.

Onecut1 is essential for horizontal cell genesis and retinal integrity.

Horizontal cells are interneurons that synapse with photoreceptors in the outer retina. Their genesis during development is subject to regulation by transcription factors in a hierarchical manner. Previously, we showed that Onecut 1 (Oc1), an atypical homeodomain transcription factor, is expressed in developing horizontal cells (HCs) and retinal ganglion cells (RGCs) in the mouse retina. Herein, by knocking out Oc1 specifically in the developing retina, we show that the majority (∼80%) of HCs fail to form during early retinal development, implying that Oc1 is essential for HC genesis. However, no other retinal cell types, including RGCs, were affected in the Oc1 knock-out. Analysis of the genetic relationship between Oc1 and other transcription factor genes required for HC development revealed that Oc1 functions downstream of FoxN4, in parallel with Ptf1a, but upstream of Lim1 and Prox1. By in utero electroporation, we found that Oc1 and Ptf1a together are not only essential, but also sufficient for determination of HC fate. In addition, the synaptic connections in the outer plexiform layer are defective in Oc1-null mice, and photoreceptors undergo age-dependent degeneration, indicating that HCs are not only an integral part of the retinal circuitry, but also are essential for the survival of photoreceptors. In sum, these results demonstrate that Oc1 is a critical determinant of HC fate, and reveal that HCs are essential for photoreceptor viability, retinal integrity, and normal visual function.

[A study on the cooperation between centers for disease control and special tuberculosis hospitals for treatment and management of multi-drug resistant tuberculosis].

OBJECTIVE: To improve the effectiveness of case detection and treatment of multi-drug resistant tuberculosis (MDR-TB) by implementing a mechanism of cooperation between hospitals and centers for disease control (CDC). METHODS: Since 1 March 2010, a new mechanism of cooperation between hospitals and CDCs had been established in 5 cities including Daqing, Quzhou, Puyang, Tianjin and Wanzhou in China. Data of MDR-TB case-detection, treatment and economic burdens before the intervention (January 1, 2006-June 30, 2009) and after the intervention (March 1, 2010-February 29, 2012) were collected. Then all data were analyzed by statistical method. RESULTS: After the intervention, samples from 68.4% (5 287/7 733) of smear-positive TB patients in the study regions underwent TB drug-resistant testing, and the number of the detected MDR-TB cases were 9.8 times that prior to the intervention. 93.1% (108/116) of the patients incorporated into the treatment of MDR-TB received the standardized initial chemotherapy program, and the number was 7 times that before the intervention. The referral rates after hospital discharge raised from 0% before the intervention to 92.8% after (90/97) the intervention; and 85.7% (83/97) of the patients received treatment and management by CDC. When the 6-month injection ended, MDR-TB patients still under treatment after the intervention were 84.5% (82/97), and those whose sputum culture became negative were 56.7% (55/97). The proportion of patients with self-paid and with catastrophic expenditures after the intervention were reduced to 18.0% (1 678/9 324) and 44.7% (17/38) respectively, as compared to 75.4% (7 659/10 158) and 76.7% (23/30) respectively before the intervention. CONCLUSION: To establish a well-performed Hospital-CDC cooperation mechanism could promote the performance of MDR-TB case detection and treatment.