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BACKGROUND AND OBJECTIVES: The estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (>25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance.RESULTS: Low TmP/GFR (CONCLUSIONS: TmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.

The currently established mechanisms of change (MOC) that explain functional improvement in cannabis use disorder (CUD) treatments are limited by an exclusive focus on abstinence, rigid definitions, and overgeneralization across populations. We aimed to move beyond these limitations by examining 1) two untested non-abstinent MOC, 2) end-of-treatment (i.e., proximal; EOT) outcomes simultaneously functioning as MOC for follow-up outcomes (i.e., distal), and 3) gender-moderated MOC and treatment progression. Participants (n = 187; 70.1% male; 57.2% White) were community members with CUD between the ages of 18-50 (M = 30.9, SD = 8.9) who participated in a 12-week multi-site pharmacotherapy trial (NCT016756612). We collected self-report data and creatinine-corrected cannabinoid urine concentrations. We tested a longitudinal path analysis to examine 1) if mid-treatment MOC (cravings and use) mediate the relationship between CUD severity at baseline and proximal outcomes (anxiety, depression, and cannabis use problems), 2) if proximal outcomes mediate the relationship between the mid-treatment MOC and a 4-week distal outcome (quality of life), and 3) if gender moderates these effects. We found that cravings are a mid-treatment MOC for the full and men sample. In women, depression functioned as a proximal outcome and a MOC for the distal outcome. Further, mid-treatment use predicted anxiety, depression, and problems at EOT for women. In contrast, mid-treatment cravings predicted depression and problems at EOT for men. The findings provide evidence for unconventional explanations of functional improvements in CUD treatment, suggesting our understanding of CUD treatment may be more complex than the literature currently suggests.

Background/Aims: Proximal colorectal cancers (CRCs) account for up to half of CRCs. Sessile serrated lesions (SSLs) are precursors to CRC. Proximal location and presence of dysplasia in SSLs predict higher risks of progression to cancer. The prevalence of dysplasia in proximal SSLs (pSSLs) and clinical characteristics of dysplastic pSSLs are not well studied.Methods: Endoscopically resected colonic polyps at our center between January 2016 and December 2017 were screened for pSSLs. Data of patients with at least one pSSL were retrieved and clinicopathological features of pSSLs were analysed. pSSLs with and without dysplasia were compared for associations.Results: Ninety pSSLs were identified, 45 of which had dysplasia giving a prevalence of 50.0%. Older age (65.9 years vs. 60.1 years, p=0.034) was associated with the presence of dysplasia. Twelve pSSLs were 10 mm or larger. After adjusting for age, pSSLs ≥10 mm had an adjusted odds ratio of 5.98 (95% confidence interval, 1.21–29.6) of having dysplasia compared with smaller pSSLs.Conclusions: In our cohort of pSSLs, the prevalence of dysplasia is high at 50.0% and is associated with lesion size ≥10 mm. Endoscopic resection for all proximal serrated lesions should be en-bloc to facilitate accurate histopathological examination for dysplasia as its presence warrants shorter surveillance intervals.

Previous work from a socio-ecological perspective reveals that ecological stress has important effects on political, cultural, and psychological outcomes. However, that work has been limited by (1) a focus on distal forms of ecological stress that are hard for societies to control, and (2) a lack of large-scale conceptual replications. The present study aims to fill in these gaps by simultaneously testing the effects of both more distal ecological stress (e.g., climate) and more proximal ecological stress (e.g., water quality) on political restriction, political freedom, well-being, and societal confidence measurements. In a sample from the Gallup World Poll spanning over one and a half million participants and 159 nations, we found that while both kinds of ecological stress measurements predicted greater vertical political restriction, reduced horizontal political restriction, reduced well-being, and reduced freedom, only proximal forms of ecological stress predicted a loss in societal confidence. These results not only provide key conceptual replications of prior studies on new data, they also add previously unstudied outcomes and new ecological stressors. As a result, they help us better understand contributing factors to key societal issues such as freedom, well-being, and societal confidence.

Dent disease 1; Cellular models Enfermedad de Dent 1; Modelos celulares Malaltia de Dent 1; Models cel·lulars Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria and variable degree of hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressing to chronic kidney disease. Although mutations in the electrogenic Cl−/H+ antiporter ClC-5, which impair endocytic uptake in proximal tubule cells, cause the disease, there is poor genotype–phenotype correlation and their contribution to proximal tubule dysfunction remains unclear. To further discover the mechanisms linking ClC-5 loss-of-function to proximal tubule dysfunction, we have generated novel DD1 cellular models depleted of ClC-5 and carrying ClC-5 mutants p.(Val523del), p.(Glu527Asp) and p.(Ile524Lys) using the human proximal tubule-derived RPTEC/TERT1 cell line. Our DD1 cellular models exhibit impaired albumin endocytosis, increased substrate adhesion and decreased collective migration, correlating with a less differentiated epithelial phenotype. Despite sharing functional features, these DD1 cell models exhibit different gene expression profiles, being p.(Val523del) ClC-5 the mutation showing the largest differences. Gene set enrichment analysis pointed to kidney development, anion homeostasis, organic acid transport, extracellular matrix organization and cell-migration biological processes as the most likely involved in DD1 pathophysiology. In conclusion, our results revealed the pathways linking ClC-5 mutations with tubular dysfunction and, importantly, provide new cellular models to further study DD1 pathophysiology. This work was supported in part by Asdent Patients Association and grants from Ministerio de Ciencia e Innovación (SAF201459945-R and SAF201789989-R to A.M.), the Fundación Senefro (SEN2019 to A.M.) and Red de Investigación Renal REDinREN (12/0021/0013). A.M. group holds the Quality Mention from the Generalitat de Catalunya (2017 SGR).

Objectives: This study aimed to investigate the techniques of matricing used by Egyptian dentists, and evaluate the influence of these techniques on the reproduction of optimum proximal contacts for posterior proximal resin composite restorations. Material and methods: An online questionnaire was developed and sent to 785 dentists via e-mail and social media platforms. The survey asked the participants about the following: the highest academic degree achieved and their experience, techniques of matricing used, brands of matricing systems used, assessment of proximal contact points, their evaluation of the contact points they reproduced, and their assessment of the restorations’ emergence profiles. Results: A total of 415 dentists participated in the study (response rate 52.8%). 308 dentists (74%) preferred using the sectional matrix system, while 107 dentists (26%) preferred using the circumferential matrix system. One hundred twenty-six dentists (31%) reported that the circumferential matrix systems reproduced optimum contacts, 105 dentists (25%) reported tight contacts and 184 dentists (44%) reported open contacts. However, for the sectional matrix systems, the optimum contacts were reported by 279 dentists (67%) tight contacts by 109 dentists (26%) and open contacts by 27 dentists (7%). There was a statistically significant difference between the sectional matrix systems and the circumferential matrix systems regarding the tightness of the proximal contact points (P

Proximal tibiofibular joint (PTFJ) pathology is an uncommon but perhaps underappreciated cause of lateral knee pain. While imaging guided therapeutic injections for diagnosis and management of joint related symptoms are now commonplace and numerous techniques for accessing most joints in the body have been documented, a technique for fluoroscopically guided injection of the PTFJ has not been yet described in the literature. We present a case of an adult patient who presented with lateral knee pain refractory to conservative management who opted for a fluoroscopically-guided therapeutic injection of her PTFJ.

Several vegetation indices (VIs) have been proposed in the literature with the objective of exploring the spectral properties of the vegetation as they are usually related to biophysical parameters of the plants. The objective of this study was to evaluate the relationship between VIs, obtained in two different RPAS platforms (Remotely-piloted spacecraft system) and proximity system at different corm growth stages with the nitrogen (N) nutritional status in the plant. Five treatments with different nitrogen fertilizer rates (20, 60, 120, 180 and 240 kg ha-1) were studied in order to generate the variability of nitrogen uptake by the plant in four blocks with five replicates each. Reading of the following VIs were performed: NDRE and NDVI (proximity sensing, Optrix sensor) and NDRE, NDVI, EVI2 and GNDVI (RPAS platform, MicaSense Parrot Sequoia sensor) at the phenological stages V5, V6, V7, V9, V11 and V12. Corn plants were collected to evaluate N content in the aerial part of the plant. The N content was higher in V7 growth stage and lower in V12 stage. The VIs obtained through the RPAS platform presented higher relationship with the corn nutritional status when compared to the proximity sensors. The V12 corn growth stage had higher relationship of VIs and plant N content in comparison to the proximity sensor. Several vegetation indices (VIs) have been proposed in the literature with the objective of exploring the spectral properties of the vegetation as they are usually related to biophysical parameters of the plants. The objective of this study was to evaluate the relationship between VIs, obtained in two different RPAS platforms (Remotely-piloted spacecraft system) and proximity system at different corm growth stages with the nitrogen (N) nutritional status in the plant. Five treatments with different nitrogen fertilizer rates (20, 60, 120, 180 and 240 kg ha-1) were studied in order to generate the variability of nitrogen uptake by the plant in four blocks with five replicates each. Reading of the following VIs were performed: NDRE and NDVI (proximity sensing, Optrix sensor) and NDRE, NDVI, EVI2 and GNDVI (RPAS platform, MicaSense Parrot Sequoia sensor) at the phenological stages V5, V6, V7, V9, V11 and V12. Corn plants were collected to evaluate N content in the aerial part of the plant. The N content was higher in V7 growth stage and lower in V12 stage. The VIs obtained through the RPAS platform presented higher relationship with the corn nutritional status when compared to the proximity sensors. The V12 corn growth stage had higher relationship of VIs and plant N content in comparison to the proximity sensor.

Objectives For an ORCA/EFCD consensus, this systematic review assessed the question “How to intervene in the caries process in proximal caries in adolescents and adults”. Material and methods Separating between the management of initial and cavitated proximal caries lesions, Medline via PubMed was searched regarding non-operative/non-invasive, minimally/micro-invasive and restorative treatment. First priority was systematic reviews or randomized controlled trials (RCTs), otherwise cohort studies. After extraction of data, the potential risk of bias was estimated depending on the study type, and the emerging evidence for conclusions was graded. Results Regarding non-invasive/non-operative care (NOC), no systematic reviews or RCTs were found. In cohort studies (n = 12) with a low level of evidence, NOC like biofilm management and fluoride was associated with a low proportion and slow speed of progression of initial proximal lesions. Minimally/micro-invasive (MI) treatments such as proximal sealants or resin infiltration (four systematic reviews/meta-analyses) were effective compared with a non-invasive/placebo control at a moderate level of evidence. Data on restorative treatment came with low evidence (5 systematic reviews, 13 RCTs); with the limitation of no direct comparative studies, sample size-weighted mean annual failure rates of class II restorations varied between 1.2 (bulk-fill composite) and 3.8% (ceramic). Based on one RCT, class II composite restorations may show a higher risk of failure compared with amalgam. Conclusions Proximal caries lesions can be managed successfully with non-operative, micro-invasive and restorative treatment according to lesion stage and caries activity. Clinical relevance Proximal caries treatment options like non-operative, micro-invasive and restorative care should be considered individually.

The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largely-redundant roles. However, whereas examination of metabolomics data from Oat-knockout mice (Oat1 and Oat3KO) revealed considerable overlap, over a hundred metabolites were increased in the plasma of one or the other of these knockout mice. Many of these relatively unique metabolites are components of distinct biochemical and signaling pathways, including those involving amino acids, lipids, bile acids, and uremic toxins. Cheminformatics, together with a “logical” statistical and machine learning-based approach, identified a number of molecular features distinguishing these unique endogenous substrates. Compared with OAT1, OAT3 tends to interact with more complex substrates possessing more rings and chiral centers. An independent “brute force” approach, analyzing all possible combinations of molecular features, supported the logical approach. Together, the results suggest the potential molecular basis by which OAT1 and OAT3 modulate distinct metabolic and signaling pathways in vivo. As suggested by the Remote Sensing and Signaling Theory, the analysis provides a potential mechanism by which “multispecific” kidney proximal tubule transporters exert distinct physiological effects. Furthermore, a strong metabolite-based machine-learning classifier was able to successfully predict unique OAT1 versus OAT3 drugs; this suggests the feasibility of drug design based on knockout metabolomics of drug transporters. The approach can be applied to other SLC and ATP-binding cassette drug transporters to define their nonredundant physiological roles and for analyzing the potential impact of drug–metabolite interactions.

Background Therapists specializing in handwriting difficulties in children often address motor problems including both proximal and distal movements in the upper extremity. Kinematic measures can be used to investigate various aspects of handwriting. This study examined differences in movement patterns in proximal and distal joints of the upper extremity during graphomotor tasks between typically developing children with and without handwriting problems. Additionally, it explored relationships between movement patterns, speed, and legibility of writing. Methods Forty-one children, aged 7–11 years, were assessed with the Aleph Aleph Ktav Yad Hebrew Handwriting assessment and the Beery Test of Visual Motor Integration and, based on their scores, were divided into a research group (with handwriting difficulties) and a control group (without handwriting difficulties). Upper extremity joint movement patterns were analyzed with a motion capture system. Differences in the quality of shapes traced and copied on a graphics tablet positioned horizontally and vertically were compared. Between-group differences and relationships with speed and legibility were analyzed. Results In both groups, there was greater movement in the distal compared to the proximal joints, greater movement when performing the task in a horizontal compared to a vertical plane, and greater movement when tracing than copying. Joint movements in the arm executed scaled-down versions of the shapes being drawn. While the amount of joint displacement was similar between groups, children in the research group showed greater dissimilarity between the drawn shape and the shape produced by the proximal joints. Finally, the drawing measure on the tablet was a significant predictor of legibility, speed of writing, visual motor integration and motor coordination, whereas the dissimilarity measure of joint movement was a significant predictor of speed of writing and motor coordination. Conclusions This study provides support for the role of the distal upper extremity joints in the writing process and some guidance to assist clinicians in devising treatment strategies for movement-related handwriting problems. While we observed differences in proximal joint movements between the children with and without handwriting difficulties, the extent to which they are responsible for the differences in drawing quality remains to be determined. Further studies should use a similar methodology to examine additional tasks such as drawing shapes of varying sizes.

Background There are persistent deficits of the proximal musculature in individuals with anterior cruciate ligament reconstruction. Previous research has shown that proximal musculature fatigue alters drop vertical jump performance in healthy individuals. It is unknown how proximal musculature fatigue will alter drop vertical jump performance in individuals who have undergone anterior cruciate ligament reconstruction. # Hypothesis/Purpose The purpose of this study was to examine the effects of a proximal extensor musculature fatigue protocol on drop vertical jump landing biomechanics of individuals with a history of anterior cruciate ligament reconstruction using both single-joint parameters and total support moment analysis. # Study Design Quasi-experimental pre-post laboratory experiment # Methods Nineteen participants with a history of unilateral anterior cruciate ligament reconstruction were recruited. Three-dimensional motion analysis was performed bilaterally during a drop vertical jump. Participants then completed a proximal extensor musculature fatigue protocol and immediately repeated the drop vertical jump task. Sagittal plane kinetics and kinematics were collected. Joint contributions to peak total support moment were calculated. A condition-by-limb repeated measures analysis of variance was performed to explore the effects of the fatigue protocol, using an alpha level of 0.05. # Results There were no interactions observed for any parameters. However, the injured limb demonstrated less vertical ground reaction force (13%, p=0.013) and reduced peak dorsiflexion angle (2°, p=0.028) both before and after the protocol. After the fatigue protocol both limbs demonstrated reduced hip extensor contribution to peak total support moment (4%, p=0.035). # Conclusions Individuals with a history of anterior cruciate ligament reconstruction performed the drop vertical jump with an altered anti-gravity support strategy after the proximal extensor musculature fatigue protocol. The significant reduction in bilateral hip extensor contribution to peak total support moment suggests evidence of targeted fatigue. # Level of Evidence III

Background Expression of Mc4r in peripheral organs indicates it has broader roles in organ homeostasis and regeneration. However, the expression and function of Mc4r in the mouse limb and digit has not been fully investigated. Our previous work showed that Mc4r−/− mice fail to regenerate the digit, but whether activation of MC4R signaling could rescue digit regeneration, or stimulate proximal digit regeneration is not clear. Results We analyzed the expression dynamics of Mc4r in the embryonic and postnatal mouse limb and digit using the Mc4r-gfp mice. We found that Mc4r-GFP is mainly expressed in the limb nerves, and in the limb muscles that are undergoing secondary myogenesis. Expression of Mc4r-GFP in the adult mouse digit is restricted to the nail matrix. We also examined the effect of α-MSH on mouse digit regeneration. We found that administration of α-MSH in the Mc4r+/− mice rescue the delayed regeneration of distal digit tip. α-MSH could rescue distal digit regeneration in denervated hindlimbs. In addition, α-MSH could stimulate regeneration of the proximally amputated digit, which is non-regenerative. Conclusions Mc4r expression in the mouse limb and digit is closely related to nerve tissues, and α-MSH/MC4R signaling has a neurotrophic role in mouse digit tip regeneration.

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone.

The usage of cisplatin, a highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH) inhibitors were shown to ameliorate this dose-limiting side effect, but both approaches have some pharmacological limitations. Analogues of EETs are an alternative avenue with unique benefits, but the current series of analogues face concerns regarding their structure and mimetic functionality. Hence, in this study, regioisomeric mixtures of four new ARA alkyl ethers were synthesized, characterized, and assessed as EET analogues against the concentration- and time-dependent toxicities of cisplatin in porcine proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy- (1), good for n-propoxy- (4), and excellent for ethoxy- (2) and i-propoxy- (3). Compounds 2 and 3 displayed cytoprotective effects comparable to that of an EET regioisomeric mixture (5) against high, acute cisplatin exposures but were more potent against low to moderate, chronic exposures. Compounds 2 and 3 (and 5) acted through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and caspase-3. This study demonstrates that alkoxy- groups are potent and more metabolically stable bioisostere alternatives to the epoxide within EETs that enable sEH-independent activity. It also illustrates the potential of ether-based mimics of EETs and other epoxy fatty acids as promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin without compromising its antineoplastic function.

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease. Although hyperglycaemia has been determined as the most important risk factor, hypoxia also plays a relevant role in the development of this disease. In this work, a comprehensive metabolomic study of the response of HK-2 cells, a human cell line derived from normal proximal tubular epithelial cells, to hyperglycemic, hypoxic diabetic-like milieu has been performed. Cells simultaneously exposed to high glucose (25 mM) and hypoxia (1% O2) were compared to cells in control conditions (5.5 mM glucose/18.6% O2) at 48 h. The combination of advanced metabolomic platforms (GC-TOF MS, HILIC- and CSH-QExactive MS/MS), freely available metabolite annotation tools, novel databases and libraries, and stringent cut-off filters allowed the annotation of 733 metabolites intracellularly and 290 compounds in the extracellular medium. Advanced bioinformatics and statistical tools demonstrated that several pathways were significantly altered, including carbohydrate and pentose phosphate pathways, as well as arginine and proline metabolism. Other affected metabolites were found in purine and lipid metabolism, the protection against the osmotic stress and the prevention of the activation of the β-oxidation pathway. Overall, the effects of the combined exposure of HK-cells to high glucose and hypoxia are reasonably compatible with previous in vivo works.

Plant water use is an important function reflecting vegetation physiological status and affects plant growth, productivity, and crop/fruit quality. Although hyperspectral vegetation indices have recently been proposed to assess plant water use, limited sample sizes for established models greatly astricts their wide applications. In this study, we have managed to gather a large volume of continuous measurements of canopy spectra through proximally set spectroradiometers over the canopy, enabling us to investigate the feasibility of using continuous narrow-band indices to trace canopy-scale water use indicated by the stem sap flux density measured with sap flow sensors. The results proved that the newly developed D (520, 560) index was optimal to capture the variation of sap flux density under clear sky conditions (R2 = 0.53), while the best index identified for non-clear sky conditions was the D (530, 575) (R2 = 0.32). Furthermore, the bands used in these indices agreed with the reported sensitive bands for estimating leaf stomatal conductance which has a critical role in transpiration rate regulation over a short time period. Our results should point a way towards using proximal hyperspectral indices to trace tree water use directly.

Introduction: Despite lack of data regarding proximal dental caries lesions, they may account for a substantial (>50%) proportion of all reported caries in some populations. Detection of proximal caries relies on clinical and radiographic examination. This study aimed to investigate the prevalence of proximal caries in posterior teeth in adults and children treated at Bristol Dental Hospital (BDH) and South Bristol Community Hospital (SBCH) in 2013. Method: Radiographs were examined and statistical analyses determined the distribution and average number of decayed proximal surfaces between 4 sample groups (BDH Adult, BDH Child, SBCH Adult, and SBCH Child). Results: Of the 178 subjects, 41.6% were free from proximal caries. Those with caries each had, on average, 3 carious proximal surfaces. There was a clear difference in the proportion of caries-free subjects between the 4 groups, which was lowest in the BDH Child group where 90% possessed at least one untreated decayed proximal surface. This may be explained by the fact that many of patients in this group are referred for multiple extractions of carious teeth.Conclusions: Posterior teeth are not uniformly affected by caries. Fewer proximal surfaces are restored than occlusal lesions possibly due to implementation of preventive treatment modalities.

Reliable measures of biomass, species composition, nitrogen status, and nutritive value provide important indicators of the status of pastures and rangelands, allowing managers to make informed decisions. Traditional methods of sample collection necessitate significant investments in time and labor. Proximal sensing technologies have the potential to collect more data with a smaller investment in time and labor. However, methods and protocols for conducting pasture assessments with proximal sensors are still in development, equipment and software vary considerably, and the accuracy and utility of these assessments differ between methods and sites. This review summarizes the methods currently being developed to assess pastures and rangelands worldwide and discusses these emerging technologies in the context of diffusion of innovation theory. Published version

Background Although surgical endarterectomy remains the treatment of choice for carotid artery stenosis, carotid artery stenting (CAS) with use of proximal protection systems (PPS) plays an very important role as alternative treatment modality, especially in patients with critical, symptomatic lesions. This study was single-centre study to evaluate the technical and clinical success of proximal protection devices as the first choice for embolic protection in symptomatic and asymptomatic carotid stenosis in patients with bilateral, advanced lesions of carotid arteries (bilateral stenoses or stenosis and occlusion). Methods This was a post hoc analysis, with 30-day follow up. We analyzed results of treatment of 38 patients who underwent 38 CAS with PPS, 17 such procedures in asymptomatic (group A), and 21 in symptomatic individuals (group B). The GORE ® Flow Reversal System (W.L. Gore, Flagstaff, AZ, USA) was used in 2 patients, and the Mo.Ma Ultra device (Medtronic, Minneapolis, MN, USA) in 36 patients. Mean age was 68 ± 7 years, 65% percent of patient were male. Results There were no procedural and during 30-day follow-up neurologic events. Intolerance of occlusion system occurred in 4 patients (11%) in both groups with any later symptoms. Risk factors of this adverse event comprised: lesions of the left internal carotid lesion and coexisiting diabetes mellitus. Conclusions CAS in high risk patients with bilateral lesions of carotid arteries with the use of PPS seems to be a relatively very safe procedure.

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the β-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression.

The cloning of the renal NaPi-2a (SLC34A1) and NaPi-2c (SLC34A3) phosphate transporters has made it possible to characterize the molecular and biophysical regulation of renal proximal tubular reabsorption of inorganic phosphate (Pi). Dietary factors, such as Pi and K, and several hormones and phosphatonins, including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and glucocorticoids, regulate the transporters through various transcriptional, translational, and post-translational mechanisms that involve acute trafficking via endocytosis or exocytosis, interactions with PDZ domain proteins, lipid microdomains, and diffusion and clustering in the apical brush border membrane. The visualization of these trafficking events by means of novel microscopy techniques that includes fluorescence lifetime imaging microscopy (FLIM), Förster resonance energy transfer (FRET), fluctuation correlation spectroscopy (FCS), and modulation tracking (MT), is the primary focus of this review.

Primary cells cultured in vitro gradually lose features characteristic of the in vivo phenotype. Culture techniques that help maintain cell-specific phenotype are advantageous for development of tissue engineered and bioartificial organs. Here we evaluated the phenotype of primary human renal tubule epithelial cells subjected to fluid shear stress by culturing the cells on an orbital shaker. Transepithelial electrical resistance, cell density, and gene and protein expression of proximal tubule specific functional markers were measured in cells subjected to orbital shear stress. Cells cultured on an orbital shaker had increased transepithelial electrical resistance, higher cell density, and enhanced tubular epithelial specific gene and protein expression. This is likely due at least in part to the mechanical stress applied to the apical surface of the cells, although other factors including increased nutrient and oxygen delivery and improved mixing could also play a role. These results suggest that orbital shaker culture may be a simple approach to augmenting the differentiated phenotype of cultured renal epithelial cells.

// Sebastian A. Garcia 1, 2 , Anka Swiersy 1 , Praveen Radhakrishnan 2 , Vittorio Branchi 3 , Lahiri Kanth Nanduri 1 , Balazs Győrffy 4, 5 , Alexander M. Betzler 1 , Ulrich Bork 1, 2 , Christoph Kahlert 1, 2 , Christoph Reisfelder 1, 2 , Nuh N. Rahbari 1, 2 , Jurgen Weitz 1, 2 , Sebastian Scholch 1, 2 1 Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Fetscherstr. 74, 01307 Dresden, Germany 2 Department of General, Gastrointestinal and Transplantation Surgery, University Hospital Heidelberg, Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany 3 Department of General, Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany 4 MTA TTK Lendulet Cancer Biomarker Research Group, Magyar Tudosok korutja 2., H-1117, Budapest, Hungary 5 Semmelweis University, 2nd Department of Pediatrics, Bokay u. 53-54., H-1083, Budapest, Hungary Correspondence to: Sebastian Scholch, email: sebastian.schoelch@uniklinikum-dresden.de Keywords: ldb1, wnt signaling, colorectal cancer, proximal, distal Received: August 15, 2016 Accepted: September 30, 2016 Published: October 05, 2016 ABSTRACT Background: Colorectal cancer (CRC) is the third most common cancer in western countries and is driven by the Wnt signaling pathway. LIM-domain-binding protein 1 ( LDB1 ) interacts with the Wnt signaling pathway and has been connected to malignant diseases. We therefore aimed to evaluate the role of LDB1 in CRC. Results: Overexpression of LDB1 in CRC is associated with strikingly reduced overall and metastasis free survival in all three independent patient cohorts. The expression of LDB1 positively correlates with genes involved in the Wnt signaling pathway ( CTNNB1 , AXIN2 , MYC and CCND1 ). Overexpression of LDB1 in CRC cell lines induced Wnt pathway upregulation as well as increased invasivity and proliferation. Upon separate analysis, the role of LDB1 proved to be more prominent in proximal CRC, whereas distal CRC seems to be less influenced by LDB1 . Materials and Methods: The expression of LDB1 was measured via RT-qPCR in 59 clinical tumor and normal mucosa samples and correlated to clinical end-points. The role of LDB1 was examined in two additional large patient cohorts from publicly available microarray and RNAseq datasets. Functional characterization was done by lentiviral overexpression of LDB1 in CRC cell lines and TOP/FOP, proliferation and scratch assays. Conclusions: LDB1 has a strong role in CRC progression, confirmed in three large, independent patient cohorts. The in vitro data confirm an influence of LDB1 on the Wnt signaling pathway and tumor cell proliferation. LDB1 seems to have a more prominent role in proximal CRC, which confirms the different biology of proximal and distal CRC.

Kidneys contribute to glucose homeostasis by reabsorbing filtered glucose in the proximal tubules via sodium-glucose cotransporters (SGLTs). Reabsorption is primarily handled by SGLT2, and SGLT2-specific inhibitors, including dapagliflozin, canagliflozin, and empagliflozin, increase glucose excretion and lower blood glucose levels. To resolve unanswered questions about these inhibitors, we developed a novel approach to map the distribution of functional SGLT2 proteins in rodents using positron emission tomography with 4-[18F]fluoro-dapagliflozin (F-Dapa). We detected prominent binding of intravenously injected F-Dapa in the kidney cortexes of rats and wild-type and Sglt1-knockout mice but not Sglt2-knockout mice, and injection of SGLT2 inhibitors prevented this binding. Furthermore, imaging revealed only low levels of F-Dapa in the urinary bladder, even after displacement of kidney binding with dapagliflozin. Microscopic ex vitro autoradiography of kidney showed F-Dapa binding to the apical surface of early proximal tubules. Notably, in vivo imaging did not show measureable specific binding of F-Dapa in heart, muscle, salivary glands, liver, or brain. We propose that F-Dapa is freely filtered by the kidney, binds to SGLT2 in the apical membranes of the early proximal tubule, and is subsequently reabsorbed into blood. The high density of functional SGLT2 transporters detected in the apical membrane of the proximal tubule but not detected in other organs likely accounts for the high kidney specificity of SGLT2 inhibitors. Overall, these data are consistent with data from clinical studies on SGLT2 inhibitors and provide a rationale for the mode of action of these drugs.

Background: The radius, also known as the radial bone, is the shorter of the two bones of the forearm. It has proximal and distal articulations with the humerus, ulna, and carpal bones. It is almost universally present,as a skeletal blueprint, in eachtetrapod’s forelimb. The detailed morphometry of radius, has not been fully explored. Specifically, the inclination of its proximal and distal articular surfaces, which can be affected in many pathologies including: fractures-dislocations, joint’s degenerations, tumors, dystrophic calcifications, and pathologic deposits.Aims and Objectives: To derive a statistical inference concerning the inclination of the proximal and distal articular surface of radius.Materials and Methods: In a sample of 30 dry specimens of human radial bone (radius), measurements were done to derive statistical inference concerning: the inclination of proximal and distal articular surfaces (P and D), length of radius (L), mid-point thickness (T), length of head of radius (HL). Materials used for measurements included: electronic Vernier, digital inclinometer, and a tape measure. The most challenging parameter to be measured, was the inclination of articular surfaces, which required multiple reference points: at the interosseous border of radius, proximal and distal ends of radius.Results: The mean values (+/- standard deviation) were: 22.23 +/- 1.89 cm (L), 1.43 +/- 0.2 cm (T), 0.95 +/- 0.135 cm (HL), 6.283 +/- 3.253 (P), and 23.77 +/- 1.874 (D). The 95% Confidence Interval was: 0.90 to 1 (HL), 5.07 to 7.50 (P), and 23.07 to 24.47 (D). Linear regression was absent between most of the studied parameters, with exception for the correlation between the inclination of the proximal articular surface and the value of (P/HL), which revealed a Correlation coefficient (r): 0.958, and the relevant p-value is < 0.00001 (significant at p< 0.01).Conclusion: This study is in line with prior studies concerning the morphometry and inclination of radial articular surfaces. It has a tremendous value in biomedical science, biomechanical applications and prosthesis synthesis, corrective surgical and orthopedic procedures, anthropology, and forensic sciences.Asian Journal of Medical Sciences Vol.7(5) 2016 117-123

Background There are many methods of treating Legg–Calvé–Perthes disease, including operative and nonoperative methods. Femoral varus osteotomy is one of the surgical methods used to treat this disease, and it involves changing the alignment of the proximal femur to improve containment of the femoral epiphysis in the acetabulum. The aims of this study were to evaluate the results of femoral varus osteotomy for the treatment of Perthes disease according to various classification and grading schemes, as well as to compare the results to those obtained using other methods of treatment reported in the literature. Materials and methods Twenty-three patients with Legg–Calvé–Perthes disease were treated using a proximal femoral varus osteotomy procedure. The mean age of the patients was 7.8 years (range: 6–11.5 years). The average follow-up was 36.2 months (range: 29–48 months). Results The patients were classified and graded according to the Catterall and Herring classifications. The preoperative and postoperative mean epiphyseal extrusion indices were as follows: group III (B), 10.88 % and 7.22 %, P = 0.027; group III (BC), 15.81 and 8.93 %, P = 0.005; group IV (C), 72.64 and 39.44 %, P = 0.018. The preoperative and the postoperative mean Wiberg’s CE angle were as follows: group III (B), 26.88° and 37.81°, P = 0.028; group III (BC), 24.4° and 32.2°, P = 0.005; group IV (C), 20.89° and 28.41°, P = 0.018. Changes in Iowa clinical hip scores were as follows: group III (B), 54.8 to 92.33, P = 0.027; group III (BC), 47.3 to 87.8, P = 0.005; group IV (C) 34.43 to 68.29, P = 0.017. In the last follow-up, the mean limb length discrepancy after plate removal was 0.9 cm (range: 0.0–2 cm) of shortening on the operated side. The author of the present study did not see any progressive change in this parameter during the follow-up period, especially after hardware removal and in the younger boys. All of the osteotomies united within 3 months without loss of fixation. Conclusion According to the results of the present study, proximal femoral varus osteotomy gives good results in children between the ages of 6 and 10 years without any femoral head deformity and flattening, especially with good containment in abduction. Level of evidence Level IV.

Background Anodal transcranial direct current stimulation (a-tDCS) can facilitate primary motor cortex (M1), but the modulation of motor evoked potentials (MEPs) by a-tDCS varies between participants, and may depend on the balance between early versus late I-wave recruitment, as assessed by the difference in MEP latency between latero-medial and anterior-posterior cortical currents induced by transcranial magnetic stimulation (TMS). Objective To date, the dependence of tDCS after-effects on I-wave recruitment has only been investigated in intrinsic hand muscles. In order to better understand the effects of tDCS across the upper limb, the present study examined I-wave recruitment and MEP modulation by a-tDCS or dual-hemisphere tDCS in muscles of the forearm (Extensor Carpi Radialis; ECR) and proximal upper limb (Biceps Brachii; BB). Methods We conducted a randomized double-blind study with 18 healthy adults. Each received anodal, dual-hemisphere, or sham tDCS over M1 in separate sessions (tDCS, 1 mA for 15 min). Results Linear regression analyzes showed a-tDCS modulated MEP size dependent on the latency difference in the ECR (P = 0.01) but not BB (P = 0.28). Individuals with small MEP latency differences showed the expected facilitation of ECR MEPs after a-tDCS, whereas those with large MEP latency differences had suppressed ECR MEPs after a-tDCS. This relationship was not present after dual-hemisphere or sham tDCS in either muscle (all P > 0.32). Conclusions I-wave recruitment can predict the after-effects of a-tDCS in the distal but not proximal upper limb. These findings provide further insight into the variability of tDCS after-effects, and the relationship between I-wave recruitment and putative mechanisms of tDCS.

Background: Total knee arthroplasty is accompanied by moderate to severe postoperative pain. Postoperative pain hampers the functional recovery and lowers patient satisfaction with the surgery. Recently, the adductor canal block (ACB) has been widely used in total knee arthroplasty. However, there is no definite answer as to the location of a continuous block within the ACBs. Method: Randomized controlled trials about relevant studies were searched in PubMed (1996 to Oct 2019), Embase (1996 to Oct 2019), and Cochrane Library (CENTRAL, Oct 2019). Results: Five studies involving 348 patients met the inclusion criteria. Pooled data indicated that the proximal ACB was as effective as the distal ACB in terms of total opioid consumption (P = .54), average visual analog scale (VAS) score (P = .35), worst VAS score (P = .19), block success rate (P = .86), and time of catheter insertion (P = .54). Conclusions: Compared with the distal ACB, the proximal ACB showed similar analgesic efficacy for total opioid consumption, average VAS score, worst VAS score, block success rate, and time of catheter insertion. However, because of the limited number of involved studies, more high-quality studies are needed to further identify the optimal location of the ACB.

Chronic kidney disease (CKD) causes anemia and impairs intestinal iron absorption. However, use of the phosphate binder ferric citrate (FC) increases body iron stores and hemoglobin levels in CKD patients. By intensifying oxidative stress and inflammation iron overload resulting from excessive use of intravenous iron can accelerate CKD progression. The present study explored the route of absorption and tissue distribution of iron with FC administration and its effect on renal function, histology, and inflammatory, oxidative, and fibrosis pathways in CKD rats. Male Sprague Dawley rats were randomized to sham-operated control (CTL) group and 5/6 nephrectomized (CKD) groups fed either regular or 4% FC-supplemented diets for 6 weeks. Animals were then sacrificed, and blood and target tissues were harvested and processed. The untreated CKD rats exhibited anemia, hypertension, upregulation of renal tissue inflammatory, oxidative, and fibrotic pathways, impaired nuclear translocation, and downregulation of Nrf2's target gene products and depletion of colonic epithelial tight junction proteins. FC administration raised serum iron, improved anemia, attenuated hyperphosphatemia, partially improved renal function, reduced oxidative stress, inflammation, and fibrosis, and restored colonic epithelial zonula occludens-1 protein abundance. Tissue iron staining detected presence of iron in epithelial cells and subepithelium of colon and in renal proximal tubules. In conclusion ferric citrate administration resulted in modest amelioration of renal function and histology and partial improvements of fibrosis, inflammation, and oxidative stress in the kidney tissues of CKD rats.

Highlights • Laparoscopic proximal gastrectomy with hinged double flap method is technically challenging. • The V-Loc™ 180 wound closure device (V-Loc; Covidien, Mansfield, MA, USA) is useful for intracoporeal reconstruction. • The use of V-Loc is safe and produce reproducible results for esophagogastrostomy closure using the hinged double flap method., Background Intracorporeal reconstruction following laparoscopic proximal gastrectomy is technically challenging. The aim of this study was to investigate the use of knotless barbed absorbable sutures in esophagogastrostomy closure using the hinged double flap method. Design & method The subjects comprised patients with gastric cancer who were scheduled to undergo laparoscopic proximal gastrectomy. The V-Loc™ 180 wound closure device (V-Loc; Covidien, Mansfield, MA, USA) was used for all laparoscopic esophagogastrostomy closures. Between January 2015 and November 2016, 13 patients were enrolled. Results The mean suturing time was 109.6 min. Median hospital stay was 14 days. One anastomotic minor leakage occurred in an esophagogastrostomy and it was managed conservatively. Twelve of 13 patients did not exhibit any symptoms of reflux esophagitis. Conclusion These results suggest the use of the unidirectional barbed absorbable suture is safe and produce reproducible results for esophagogastrostomy closure using the hinged double flap method.

Renal tubular acidosis (RTA) represents a group of diseases characterized by (1) a normal anion gap metabolic acidosis; (2) abnormalities in renal HCO3− absorption or new renal HCO3− generation; (3) changes in renal NH4+, Ca2+, K+, and H2O homeostasis; and (4) extrarenal manifestations that provide etiologic diagnostic clues. The focus of this review is to give a general overview of the pathogenesis of the various clinical syndromes causing RTA with a particular emphasis on type I (hypokalemic distal RTA) and type II (proximal) RTA while reviewing their pathogenesis from a physiological "bottom-up" approach. In addition, the factors involved in the generation of metabolic acidosis in both type I and II RTA are reviewed highlighting the importance of altered renal ammonia production/partitioning and new HCO3− generation. Our understanding of the underlying tubular transport and extrarenal abnormalities has significantly improved since the first recognition of RTA as a clinical entity because of significant advances in clinical acid-base chemistry, whole tubule and single-cell H+/base transport, and the molecular characterization of the various transporters and channels that are functionally affected in patients with RTA. Despite these advances, additional studies are needed to address the underlying mechanisms involved in hypokalemia, altered ammonia production/partitioning, hypercalciuria, nephrocalcinosis, cystic abnormalities, and CKD progression in these patients.

Proximal humerus fractures constitute a significant percentage of fragility fractures. The growing use of locking plate has helped treat this problem, but at the same time has brought about complications. Past systematic reviews have documented these complications, however a large number of recent studies have been published since, reporting their own complication rates with different techniques. This study reviews the current complications associated with locking plate of proximal humerus fractures as well as methods to reduce them. A systematic review, following the PRISMA guidelines, was conducted in November 2013 and repeated in March 2015, using PubMed, Scopus, and Cochrane databases, to evaluate locking plate fixation (and complications) of traumatic proximal humerus fractures. Inclusion criteria included adults (>18 years), minimum of 12-month postoperative followup, articles within the last 5 years, and studies with >10 participants. Exclusion criteria included pathologic fractures, cadaveric studies, and nonhuman subjects. Eligible studies were graded using a quality scoring system. Articles with a minimum of 7/10 score were included and assessed regarding their level of evidence per the Journal of Bone and Joint Surgery and Centre for Evidence-Based Medicine guidelines. The initial query identified 51,206 articles from multiple databases. These records were thoroughly screened and resulted in 57 articles, consisting of seven Level 1, three Level 2, 10 Level 3, and 37 Level 4 studies, totaling 3422 proximal humerus fractures treated with locking plates. Intraarticular screw penetration was the most reported complication (9.5%), followed by varus collapse (6.8%), subacromial impingement (5.0%), avascular necrosis (4.6%), adhesive capsulitis (4.0%), nonunion (1.5%), and deep infection (1.4%). Reoperation occurred at a rate of 13.8%. Collapse at the fracture site contributed to a majority of the implant-related complications, which in turn were the main reasons for reoperation. The authors of these studies discussed different techniques that could be used to address these issues. Expanding use of locking plate in the proximal humerus fractures leads to improvements and advancements in surgical technique. Further research is necessary to outline indications to decrease complications, further.

Traditional treatments for type 1 and type 2 diabetes are often associated with side effects, including weight gain and hypoglycaemia that may offset the benefits of blood glucose lowering. The kidneys filter and reabsorb large amounts of glucose, and urine is almost free of glucose in normoglycaemia. The sodium-dependent glucose transporter (SGLT)-2 in the early proximal tubule reabsorbs the majority of filtered glucose. Remaining glucose is reabsorbed by SGLT1 in the late proximal tubule. Diabetes enhances renal glucose reabsorption by increasing the tubular glucose load and the expression of SGLT2 (as shown in mice), which maintains hyperglycaemia. Inhibitors of SGLT2 enhance urinary glucose excretion and thereby lower blood glucose levels in type 1 and type 2 diabetes. The load-dependent increase in SGLT1-mediated glucose reabsorption explains why SGLT2 inhibitors in normoglycaemic conditions enhance urinary glucose excretion to only ~50% of the filtered glucose. The role of SGLT1 in both renal and intestinal glucose reabsorption provides a rationale for the development of dual SGLT1/2 inhibitors. SGLT2 inhibitors lower blood glucose levels independent of insulin and induce pleiotropic actions that may be relevant in the context of lowering cardiovascular risk. Ongoing long-term clinical studies will determine whether SGLT2 inhibitors have a safety profile and exert cardiovascular benefits that are superior to traditional agents.

With the rise of automated vehicles, car drivers will be given the opportunity to perform other tasks or activities than controlling the vehicle. However, in a car that is not entirely automated, a human driver might need to manually take over control at some point. When such a situation occurs, awareness of the traffic situation is considered essential. In this study, we evaluate a design that aims to enable the driver of an automated car to perform a task (other than driving) while still gaining situation awareness through peripheral light signals. The results show that proximal peripheral light signals can increase the situation awareness of a driver while performing an alternative task or activity.

Objective: The aim of this study was to evaluate the clinical results of T-plate fixation and anterior sternoclavicular ligament repair in proximal clavicle fractures. Methods: Between August 2013 and August 2016, a total 12 patients (10 men and 2 women; mean age: 44.1 ± 9.1 years (range, 25–59 years)) with unstable proximal clavicle fractures (Throckmorton, type D) were treated with T-type plate fixation, bridging the sternoclavicular joint, and anterior sternoclavicular ligament repair. Average operative time, associated injuries, postoperative complications, postoperative fracture healing time and follow-up time were recorded. The outcomes were evaluated with radiographic assessment, visual analog scale (VAS) pain score and Rockwood SCJ scoring system. All the patients were evaluated on postoperative 3rd, 6th, and 12th months. Results: The average surgery time was 78.0 ± 8.47 minutes while fracture healing time was 4.51 ± 0.95 months. According to Rockwood SCJ scoring system, 9 cases (75%) were in excellent, 2 cases (16.7%) in good and 1 case (8.3%) in fair condition at 12 months follow-up. The average Rockwood SCJ score was 7.7 ± 0.75 preoperatively, 12.7 ± 0.86 by 3 months, 13.0 ± 0.73 by 6 months and 13.3 ± 0.49 by 12 months. The VAS pain score was 7.9 ± 1.15 (preoperative score), 3.4 ± 1.52 (3 months follow-up), 3.0 ± 1.32 (6 months follow-up) and 2.1 ± 1.07 (12 months follow-up). The VAS and Rockwood SCJ scores were significantly improved postoperatively (p

Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.

Soluble epoxide hydrolase (sEH) catalyzes the conversion of epoxyeicosatrienoic acids into less active eicosanoids, and inhibitors of sEH have anti-inflammatory and antiapoptotic properties. Based on previous observations that sEH inhibition attenuates cisplatin-induced nephrotoxicity by modulating nuclear factor-κB signaling, we hypothesized that this strategy would also attenuate cisplatin-induced renal apoptosis. Inhibition of sEH with AR9273 [1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea)] reduced cisplatin-induced apoptosis through mechanisms involving mitochondrial apoptotic pathways and by reducing reactive oxygen species. Renal mitochondrial Bax induction following cisplatin treatment was significantly decreased by treatment of mice with AR9273 and these antiapoptotic effects involved p38 mitogen-activated protein kinase signaling. Similar mechanisms contributed to reduced apoptosis in Ephx2(-/-) mice treated with cisplatin. Moreover, in pig kidney proximal tubule cells, cisplatin-induced mitochondrial trafficking of Bax and cytochrome c, caspase-3 activation, and oxidative stress are significantly attenuated in the presence of epoxyeicosatrienoic acids (EETs). Collectively, these in vivo and in vitro studies demonstrate a role for EETs in limiting cisplatin-induced renal apoptosis. Inhibition of sEH represents a novel therapeutic strategy for protection against cisplatin-induced renal damage.

DNA damage activates nuclear Abl tyrosine kinase to stimulate intrinsic apoptosis in cancer cell lines and mouse embryonic stem cells. To examine the in vivo function of nuclear Abl in apoptosis, we generated Abl-μNLS (μ, mutated in nuclear localization signals) mice. We show here that cisplatin-induced apoptosis is defective in the renal proximal tubule cells (RPTC) from the Ablμ/μmice. When injected with cisplatin, we found similar levels of platinum in the Abl+/+and the Ablμ/μkidneys, as well as similar initial inductions of p53 and PUMAα expression. However, the accumulation of p53 and PUMAα could not be sustained in the Ablμ/μkidneys, leading to reductions in renal apoptosis and tubule damage. Co-treatment of cisplatin with the Abl kinase inhibitor, imatinib, reduced the accumulation of p53 and PUMAα in the Abl+/+but not in the Ablμ/μkidneys. The residual apoptosis in the Ablμ/μmice was not further reduced in the Ablμ/μ; p53-/-double-mutant mice, suggesting that nuclear Abl and p53 are epistatic to each other in this apoptosis response. Although apoptosis and tubule damage were reduced, cisplatin-induced increases in phospho-Stat-1 and blood urea nitrogen were similar between the Abl+/+and the Ablμ/μkidneys, indicating that RPTC apoptosis is not the only factor in cisplatin-induced nephrotoxicity. These results provide in vivo evidence for the pro-apoptotic function of Abl, and show that its nuclear localization and tyrosine kinase activity are both required for the sustained expression of p53 and PUMAα in cisplatin-induced renal apoptosis. © 2013 Macmillan Publishers Limited.

Renal cell carcinomas (RCC) are a heterogeneous group of tumors with a wide range of aggressiveness. Noninvasive methods to confidently predict the tumor biologic behavior and select appropriate treatment are lacking. Here, we investigate the dynamic metabolic flux in living RCC cells using hyperpolarized 13C-pyruvate magnetic resonance spectroscopy (MRS) combined with a bioreactor platform and interrogated the biochemical basis of the MRS data with respect to cancer aggressiveness. RCC cells have significantly higher pyruvate-to-lactate flux than the normal renal tubule cells. Furthermore, a key feature distinguishing the localized from the metastatic RCC cells is the lactate efflux rate, mediated by the monocarboxylate transporter 4 (MCT4). The metastatic RCC cells have significantly higher MCT4 expression and corresponding higher lactate efflux, which is essential for maintaining a high rate of glycolysis. We show that such differential cellular transporter expression and associated metabolic phenotype can be noninvasively assessed via real-time monitoring of hyperpolarized 13C-pyruvate-to-lactate flux. Cancer Res; 73(2); 529–38. ©2012 AACR.

BackgroundTenofovir disoproxil fumarate (TDF) can cause proximal tubular damage and chronic kidney disease in human immunodeficiency virus (HIV)-infected individuals. Urine α1-microglobulin (A1M), a low-molecular-weight protein indicative of proximal tubular dysfunction, may enable earlier detection of TDF-associated tubular toxicity.Study designCross-sectional.Setting & participants883 HIV-infected and 350 -uninfected men enrolled in the Multicenter AIDS Cohort Study.PredictorsHIV infection and TDF exposure.OutcomeUrine A1M level.ResultsUrine A1M was detectable in 737 (83%) HIV-infected and 202 (58%) -uninfected men (P

BackgroundThe primary biomarkers used to define CKD are serum creatinine and albuminuria. These biomarkers have directed focus on the filtration and barrier functions of the kidney glomerulus even though albuminuria results from tubule dysfunction as well. Given that proximal tubules make up ∼90% of kidney cortical mass, we evaluated whether a sensitive and specific marker of proximal tubule injury, urinary kidney injury molecule-1 (KIM-1), is elevated in individuals with CKD or with risk factors for CKD.MethodsWe measured urinary KIM-1 in participants of five cohort studies from the USA and Sweden. Participants had a wide range of kidney function and were racially and ethnically diverse. Multivariable linear regression models were used to test the association of urinary KIM-1 with demographic, clinical and laboratory values.ResultsIn pooled, multivariable-adjusted analyses, log-transformed, creatinine-normalized urinary KIM-1 levels were higher in those with lower eGFR {β = -0.03 per 10 mL/min/1.73 m(2) [95% confidence interval (CI) -0.05 to -0.02]} and greater albuminuria [β = 0.16 per unit of log albumin:creatinine ratio (95% CI 0.15-0.17)]. Urinary KIM-1 levels were higher in current smokers, lower in blacks than nonblacks and lower in users versus nonusers of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.ConclusionProximal tubule injury appears to be an integral and measurable element of multiple stages of CKD.

Calorie restriction (CR) has been repeatedly shown to prevent cancer, diabetes, hypertension, and other age-related diseases in a wide range of animals, including non-human primates and humans. In rodents, CR also increases lifespan and is a powerful tool for studying the aging process. Recently, it has been reported in mice that dietary fat plays an important role in determining lifespan extension with 40% CR. In these conditions, animals fed lard as dietary fat showed an increased longevity compared with mice fed soybean or fish oils. In this paper, we study the effect of these dietary fats on structural and physiological parameters of kidney from mice maintained on 40% CR for 6 and 18 months. Analyses were performed using quantitative electron microcopy techniques and protein expression in Western blots. CR mitigated most of the analyzed age-related parameters in kidney, such as glomerular basement membrane thickness, mitochondrial mass in convoluted proximal tubules and autophagic markers in renal homogenates. The lard group showed improved preservation of several renal structures with aging when compared to the other CR diet groups. These results indicate that dietary fat modulates renal structure and function in CR mice and plays an essential role in the determination of health span in rodents., Supported by NIH grant 1R01AG028125 (to JJR, PN, and JMV), Ministerio de Economía y Competitividad BFU2011‐23578 (to JMV) and DEP2012‐39985 (to GL‐L), Junta de Andalucía Proyectos de Excelencia grant P09‐CVI‐4887 (to JMV), Junta de Andalucía Proyectos Internacionales (to JMV), BIO‐276 (Junta de Andalucía and the University of Córdoba, to JMV) and Fondo de Investigaciones Sanitarias FIS PI14‐01962 (to PN). RdC is supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health. MC‐R is funded by predoctoral fellowship of the Spanish Ministerio de Educación and by BIO‐276.

Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression. In addition, activation of AMPK by AICAR resulted in an increase raptor phosphorylation at Ser792 and leads to increase the promoter activity of OGG1 through upregulation of Nrf2. Downregulation of AMPK by DN-AMPK and raptor and Nrf2 by siRNA resulted in significant decease in promoter activity and protein expression of OGG1. On the other hand, downregulation of Akt by DN-Akt and rictor by siRNA resulted in significant increase in promoter activity and protein expression of Nrf2 and OGG1. Moreover, gel shift analysis shows reduction of Nrf2 binding to OGG1 promoter in cells treated with HG while cells treated with AICAR reversed the effect of HG. Furthermore, db/db mice treated with AICAR show significant increased in AMPK and raptor phosphroylation as well as OGG1 and Nrf2 protein expression that associated with significant decrease in oxidative DNA damage (8-oxodG) compared to non-treated mice. In summary, our data provide a novel protective mechanism by which AICAR prevents renal cell damage in diabetes and the consequence complications of hyperglycemia with a specific focus on nephropathy.

Aufgrund der speziellen Anatomie des Milchgebisses entziehen sich kariöse Läsionen im Approximalbereich von Milchmolaren oftmals der Diagnose mittels visueller und taktiler Inspektion. Da hier ein Erkennen der Krankheit im Initialstadium besonders wichtig ist, ist der Einsatz weiterer diagnostischer Hilfsmittel von großer Bedeutung. Die Firma KaVo bietet mit dem DIAGNOdent pen 2190 ein Werkzeug, das mithilfe der Laserfluoreszenztechnik auch die Kariesdetektion im Zahnzwischenraum ermöglichen soll beziehungsweise kann. Die vorliegende Studie untersucht die Leistungsfähigkeit und diagnostische Wertigkeit des DIAGNOdent pen im Approximalbereich zwischen dem ersten und zweiten Milchmolaren. Die Resultate werden der visuellen und taktilen Inspektion nach Separierung der Zähne gegenübergestellt. Bei 58 Patienten im Alter von 3 bis 11 Jahren wurden insgesamt 218 Approximalflächen mit dem DIAGNOdent pen untersucht. Sowohl mit der handelsüblichen Approximalraumsonde als auch mit einer graziler gestalteten Forschungssonde wurden jeweils drei Messungen von oral und von vestibulär durchgeführt und gemittelt. Die Messungen wurden nach Separierung der Zähne mittels Separiergummi wiederholt. Es folgten die visuelle Inspektion und die taktile Befundung der nun zugänglichen Zahnflächen, die die Grundlage für die finale Diagnose bildeten. Zur Interpretation der Messwerte wurde die vom Hersteller für den Approximalraum empfohlene Klassifizierung verwendet. Mit dem entsprechenden Schwellenwert von 7, der eine kariesfreie von einer initial erkrankten Zahnfläche unterscheiden soll, erreichte das Gerät eine Sensitivität von 41,4 % für die herkömmliche Approximalraumsonde beziehungsweise 45,7 % für die Forschungssonde. Die Spezifität betrug 96,1 % respektive 97,1 %. Weiterhin wurden der positive prädiktive Wert (92,3 % beziehungsweise 94,6 %), der negative prädiktive Wert (59 % beziehungsweise 61,1 %) und der Kappa- Koeffizient (0,361 beziehungsweise 0,413) für diese Einteilung ermittelt. Die ROC-Analysen lassen vermuten, dass eine sensiblere Einteilung der Werte für eine Kariesfrüherkennung im Milchgebiss sinnvoll sein könnte. Kumulative Effekte benachbarter Zähne mit Karies wurden nicht festgestellt. Rückschlüsse auf die Oberflächenbeschaffenheit einer Läsion anhand der Messwerte lassen sich ansatzweise ziehen, das heißt eine gewisse Korrelation besteht, jedoch kann nicht verlässlich von den Werten auf die Läsionsausprägung geschlossen werden. Diese Schlussfolgerungen müssen vom Behandler kritisch betrachtet werden und sollten stets unter Einbeziehung aller Kariesrisikofaktoren des Patienten geschehen. Laut Spearman-Koeffizient (0,479 beziehungsweise 0,347) besteht ein nur schwacher Zusammenhang zwischen DIAGNOdent-Wert und Läsionstiefe. Zusammenfassend kann für die hier untersuchten Approximalflächen von Milchmolaren gesagt werden, dass der DIAGNOdent pen 2190 eine wertvolle Ergänzung im Bereich der Karies-diagnostik darstellt, jedoch ohne andere Methoden überflüssig zu machen. Die kritische Interpretation der Messwerte kann bei der Untersuchung von Milchmolaren im Approximalbereich wertvolle Informationen liefern, ohne dabei einen Nachteil für den Patienten zu haben. In Kombination mit anderen diagnostischen Verfahren kann mit dem KaVo DIAGNOdent pen eine höhere Therapiesicherheit erlangt werden., Due to the special anatomy of the deciduous dentition carious lesions in the proximal spaces of primary molars often elude the diagnosis by clinical inspection. As a recognition of the disease in the initial stage is particularly important the use of other diagnostic tools is necessary. KaVo offers the DIAGNOdent pen 2190 to detect caries in the interdental space using the laser fluorescence technique. The present study investigates the performance of the DIAGNOdent pen in the approximal area between the first and second primary molars. The results are compared with the visual and tactile inspection after separation of the teeth. In 58 patients, aged 3-11 years, a total of 218 approximal surfaces with the DIAGNOdent pen were examined. Both with the standard proximal detection tip and with a gracile designed research probe three measurements were made by oral and vestibular. The measurements were repeated after separation of the teeth by inserting an orthodontic rubber ring. This was followed by visual and tactile inspection of the meanwhile accessible tooth surfaces, which formed the basis for the final diagnosis. With the recommended threshold value of 7, which differs a caries-free from an initially diseased tooth surface, the device achieved a sensitivity of 41.4 % for the conventional probe and 45.7 % for the research probe. The specificity was 96.1 % and 97.1 %, respectively. The positive predictive value (92.3 % and 94.6 %, respectively), negative predictive value (59.0 % and 61.1 %, respectively) and kappa coefficient (0.361 and 0.413, respectively) were determined. The ROC analyses suggest that a more sensitive classification for an early caries detection in the primary dentition could be useful. Cumulative effects of adjacent teeth with caries were not found. A valuation of the surface state of a lesion can be drawn to some extent. But it can not be reliably concluded by the measurements on the constitution of the lesion. These conclusions must be considered critical and should be done with the involvement of all caries risk factors of the patient. According to Spearman's coefficient (0.479 and 0.347, respectively) there is a weak correlation between DIAGNOdent value and lesion depth. In conclusion the DIAGNOdent pen 2190 is a valuable addition for proximal caries diagnosis in deciduous molars, but without making other methods unnecessary. The critical interpretation of the measured values can provide valuable information in the examination of proximal surfaces of primary molars without giving a disadvantage for the patient. In combination with other diagnostic procedures the dentist may obtain a higher therapeutic safety with the help of the DIAGNOdent pen.

Purpose of reviewThe sodium glucose cotransporter 2 (SGLT2) reabsorbs most of the glucose filtered by the kidneys. SGLT2 inhibitors reduce glucose reabsorption, thereby lowering blood glucose levels, and have been approved as new antihyperglycemic drugs. Although the therapeutic strategy is very promising, many questions remain.Recent findingsUsing validated antibodies, SGLT2 expression was localized to the brush border of the early proximal tubule in the human kidney and was found upregulated in genetic murine models of type 1 and 2 diabetes. SGLT2 may functionally interact with the Na/H exchanger NHE3 in the proximal tubule. SGLT1-mediated reabsorption explains the fractional renal glucose reabsorption of 40-50% during SGLT2 inhibition. SGLT2 is expressed on pancreatic alfa cells where its inhibition induces glucagon secretion. SGLT2 inhibition lowers glomerular filtration rate in hyperfiltering diabetic patients consistent with the tubular hypothesis of diabetic hyperfiltration. New data indicate a potential of SGLT2 inhibition for renal medullary hypoxia and ketoacidosis, but also for blood glucose effect-dependent and independent nephroprotective actions, renal gluconeogenesis inhibition, reduction in cardiovascular mortality, and cancer therapy.SummaryThe findings expand and refine our understanding of SGLT2 and its inhibition, have relevance for clinical practice, and will help interpret ongoing clinical trials on the long-term safety and cardiovascular effects of SGLT2 inhibitors.

Radford R, Slattery C, Jennings P, Blaque O, Pfaller W, Gmuender H, Van Delft J, Ryan MP, McMorrow T. Carcinogens induce loss of the primary cilium in human renal proximal tubular epithelial cells independently of effects on the cell cycle. Am J Physiol Renal Physiol 302: F905-F916, 2012. First published January 18, 2011; doi: 10.1152/ajprenal.00427.2011.-The primary cilium is an immotile sensory and signaling organelle found on the majority of mammalian cell types. Of the multitude of roles that the primary cilium performs, perhaps some of the most important include maintenance of differentiation, quiescence, and cellular polarity. Given that the progression of cancer requires disruption of all of these processes, we have investigated the effects of several carcinogens on the primary cilium of the RPTEC/TERT1 human proximal tubular epithelial cell line. Using both scanning electron microscopy and immunofluorescent labeling of the ciliary markers acetylated tubulin and Arl13b, we confirmed that RPTEC/TERT1 cells express primary cilium upon reaching confluence. Treatment with the carcinogens ochratoxin A (OTA) and potassium bromate (KBrO3) caused a significant reduction in the number of ciliated cells, while exposure to nifedipine, a noncarcinogenic renal toxin, had no effect on primary cilium expression. Flow cytometric analysis of the effects of all three compounds on the cell cycle revealed that only KBrO3 resulted in an increase in the proportion of cells entering the cell cycle. Microarray analysis revealed dysregulation of multiple pathways affecting ciliogenesis and ciliary maintenance following OTA and KBrO3 exposure, which were unaffected by nifedipine exposure. The primary cilium represents a unique physical checkpoint with relevance to carcinogenesis. We have shown that the renal carcinogens OTA and KBrO3 cause significant deciliation in a model of the proximal tubule. With KBrO3, this was followed by reentry into the cell cycle; however, deciliation was not found to be associated with reentry into the cell cycle following OTA exposure. Transcriptomic analysis identified dysregulation of Wnt signaling and ciliary trafficking in response to OTA and KBrO3 exposure.

Chronic exposure to propiverine, a frequently prescribed pharmaceutical for treatment of overactive bladder and incontinence, provokes massive protein accumulation in the cytosol and nucleus of renal proximal tubule epithelial cells in rats. Previously, the accumulating protein was identified as D-amino acid oxidase (DAAO), a peroxisomal flavoenzyme expressed in kidney, liver and brain. The cellular mechanism of propiverine-induced DAAO accumulation, however, remains unexplained and poorly characterized. Therefore, to further increase the understanding of DAAO accumulation in rat kidney, this study aimed to characterize DAAO accumulations using differential immunofluorescent staining of rat kidney sections as well as in vitro binding analyses and proteasomal activity studies. We demonstrated that propiverine is neither a ligand of DAAO nor an inhibitor of the proteasome in vitro. However, propiverine treatment resulted in a significant decrease of peroxisomal size in rat proximal tubule epithelial cells. Moreover, peroxisomal catalase also accumulated in the cytosol and nuclei of propiverine-treated rats concurrently with DAAO. Taken together, our study indicates that propiverine treatment affects the trafficking and/or degradation of peroxisomal proteins such as DAAO and catalase by a so far unique and unknown mechanism. published

International audience; PURPOSE:The aim of this study was to evaluate the short- and medium-term results of non-operative treatment of four-part fractures of the proximal end of the humerus. The initial hypothesis was that non-operative treatment of fractures with little or no displacement is equivalent or superior to surgical treatment, and that non-operative treatment is probably insufficient for displaced fractures.METHODS:This was a multicentric, prospective and retrospective study, based on 384 four-part proximal humerus fractures, 58 of which involved non-operative treatments - 37 in the prospective study (Pro-CT4) and 21 in the retrospective study (Retro-CT4). The average patient age was 64 +/- 14 years (39-90); 66 % were female and 34 % male. In 88 % of these cases, non-operative treatment was chosen for the fracture, as there was little or no displacement. In 10 % of cases, non-operative treatment was chosen "by default", due to the patient's medical conditions, as surgery was contraindicated, and in 2 % of cases due to the patient refusing surgery. All patients were reviewed clinically and radiologically, with SSV evaluation, absolute and weighted Constant scores and the Quick DASH score all assessed. The main evaluation criterion was the weighted Constant score which was considered a failure when below 70 %.RESULTS:In the Pro-CT4 study, the average follow-up period was 11 +/- four months (5-18) with functional scores as follows: average SSV: 72 +/- 26 % (8-100); average Constant score: 65 +/- 21 points (21-95); average weighted Constant score: 86 +/- 26 % (32-130); average Quick DASH: 23 +/- 21 (0-64). 27 % of patients had a weighted Constant score below 70 %. In the Retro-CT4 study, the average follow-up period was 38 +/- 13 months (18-62) with functional scores as follows: average SSV: 73 +/- 17 % (30-100); average Constant score: 68 +/- 18 points (33-95); average weighted Constant score: 88 +/- 27 % (47-133); average Quick DASH: 18 +/- 16 (0-48); 24 % of patients had a weighted Constant score below 70 %.CONCLUSION:This study confirms our initial hypothesis. When non-operative treatment of four-part proximal humerus fractures is carried out by choice, the results are excellent. However, when this treatment is carried out "by default" - especially because surgery is contraindicated - the results are disappointing.LEVEL OF EVIDENCE IV:prospective and retrospective studies

The hepatocyte nuclear factors, Hnf1a and Hnf4a, in addition to playing key roles in determining hepatocyte fate, have been implicated as candidate lineage-determining transcription factors in the kidney proximal tubule (PT) [Martovetsky et. al., (2012) Mol Pharmacol 84:808], implying an additional level of regulation that is potentially important in developmental and/or tissue-engineering contexts. Mouse embryonic fibroblasts (MEFs) transduced with Hnf1a and Hnf4a form tight junctions and express multiple PT drug transporters (e.g., Slc22a6/Oat1, Slc47a1/Mate1, Slc22a12/Urat1, Abcg2/Bcrp, Abcc2/Mrp2, Abcc4/Mrp4), nutrient transporters (e.g., Slc34a1/NaPi-2, Slco1a6), and tight junction proteins (occludin, claudin 6, ZO-1/Tjp1, ZO-2/Tjp2). In contrast, the coexpression (with Hnf1a and Hnf4a) of GATA binding protein 4 (Gata4), as well as the forkhead box transcription factors, Foxa2 and Foxa3, in MEFs not only downregulates PT markers but also leads to upregulation of several hepatocyte markers, including albumin, apolipoprotein, and transferrin. A similar result was obtained with primary mouse PT cells. Thus, the presence of Gata4 and Foxa2/Foxa3 appears to alter the effect of Hnf1a and Hnf4a by an as-yet unidentified mechanism, leading toward the generation of more hepatocyte-like cells as opposed to cells exhibiting PT characteristics. The different roles of Hnf4a in the kidney and liver was further supported by reanalysis of ChIP-seq data, which revealed Hnf4a colocalization in the kidney near PT-enriched genes compared with those genes enriched in the liver. These findings provide valuable insight, not only into the developmental, and perhaps organotypic, regulation of drug transporters, drug-metabolizing enzymes, and tight junctions, but also for regenerative medicine strategies aimed at restoring the function of the liver and/or kidney (acute kidney injury, AKI; chronic kidney disease, CKD).