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Eccrine angiomatous hamartoma is an uncommon, benign clinical entity constituting a nodular proliferation of eccrine glands and vascular structures localized to the dermis that typically present as unilateral, flesh-colored, erythematous, or violaceous papules on the extremities. These hamartomas may be associated with pain, hyperhidrosis, joint deformity, or functional impairment depending on the severity of the disease process. We present a case of bilaterally symmetric, asymptomatic eccrine angiomatous hamartomas involving all proximal interphalangeal joints of both hands. To date, there are only four prior cases of bilaterally symmetric eccrine angiomatous hamartomas reported in the literature, suggesting that the distribution experienced by our patient may represent a previously undescribed syndrome.

Background Colon cancer incidence is rising globally, and factors pertaining to urbanization have been proposed involved in this development. Traffic noise may increase colon cancer risk by causing sleep disturbance and stress, thereby inducing known colon cancer risk-factors, e.g. obesity, diabetes, physical inactivity, and alcohol consumption, but few studies have examined this. Objectives The objective of this study was to investigate the association between traffic noise and colon cancer (all, proximal, distal) in a pooled population of 11 Nordic cohorts, totaling 155,203 persons. Methods We identified residential address history and estimated road, railway, and aircraft noise, as well as air pollution, for all addresses, using similar exposure models across cohorts. Colon cancer cases were identified through national registries. We analyzed data using Cox Proportional Hazards Models, adjusting main models for harmonized sociodemographic and lifestyle data. Results During follow-up (median 18.8 years), 2757 colon cancer cases developed. We found a hazard ratio (HR) of 1.05 (95% confidence interval (CI): 0.99–1.10) per 10-dB higher 5-year mean time-weighted road traffic noise. In sub-type analyses, the association seemed confined to distal colon cancer: HR 1.06 (95% CI: 0.98–1.14). Railway and aircraft noise was not associated with colon cancer, albeit there was some indication in sub-type analyses that railway noise may also be associated with distal colon cancer. In interaction-analyses, the association between road traffic noise and colon cancer was strongest among obese persons and those with high NO2-exposure. Discussion A prominent study strength is the large population with harmonized data across eleven cohorts, and the complete address-history during follow-up. However, each cohort estimated noise independently, and only at the most exposed façade, which may introduce exposure misclassification. Despite this, the results of this pooled study suggest that

BACKGROUND: The proximal tubules eliminate protein-bound toxins and drugs through secretion. Measurements or estimates of GFR do not necessarily reflect the physiologically distinct process of secretion. Clinical assessment of this important intrinsic kidney function requires endogenous markers that are highly specific for secretory transport. METHODS: We used metabolomics profiling to identify candidate markers of tubular secretory clearance in 50 participants from a kidney pharmacokinetics study. We measured metabolites in three sequential plasma samples and a concurrent 10-hour timed urine sample using hydrophilic interaction liquid chromatography/high-resolution mass spectrometry. We quantified the association between estimated kidney clearance and normalized plasma peak height of each candidate solute to the clearance of administered furosemide, a protein-bound, avidly secreted medication. RESULTS: We identified 528 metabolites present in plasma and urine, excluding pharmaceuticals. We found seven highly (>50%) protein-bound and 49 poorly bound solutes with clearances significantly associated with furosemide clearance and 18 solute clearances favoring an association with furosemide clearance by the 90th percentile compared with GFR. We also found four highly bound and 42 poorly bound plasma levels that were significantly associated with furosemide clearance. CONCLUSIONS: We found several candidate metabolites whose kidney clearances or relative plasma levels are highly associated with furosemide clearance, an avidly secreted tracer medication of the organic anion transporters, highlighting their potential as endogenous markers of proximal tubular secretory clearance.

Background: Colon cancer incidence is rising globally, and factors pertaining to urbanization have been proposed involved in this development. Traffic noise may increase colon cancer risk by causing sleep disturbance and stress, thereby inducing known colon cancer risk-factors, e.g. obesity, diabetes, physical inactivity, and alcohol consumption, but few studies have examined this. Objectives: The objective of this study was to investigate the association between traffic noise and colon cancer (all, proximal, distal) in a pooled population of 11 Nordic cohorts, totaling 155,203 persons. Methods: We identified residential address history and estimated road, railway, and aircraft noise, as well as air pollution, for all addresses, using similar exposure models across cohorts. Colon cancer cases were identified through national registries. We analyzed data using Cox Proportional Hazards Models, adjusting main models for harmonized sociodemographic and lifestyle data. Results: During follow-up (median 18.8 years), 2757 colon cancer cases developed. We found a hazard ratio (HR) of 1.05 (95% confidence interval (CI): 0.99–1.10) per 10-dB higher 5-year mean time-weighted road traffic noise. In sub-type analyses, the association seemed confined to distal colon cancer: HR 1.06 (95% CI: 0.98–1.14). Railway and aircraft noise was not associated with colon cancer, albeit there was some indication in sub-type analyses that railway noise may also be associated with distal colon cancer. In interaction-analyses, the association between road traffic noise and colon cancer was strongest among obese persons and those with high NO2-exposure. Discussion: A prominent study strength is the large population with harmonized data across eleven cohorts, and the complete address-history during follow-up. However, each cohort estimated noise independently, and only at the most exposed façade, which may introduce exposure misclassification. Despite this, the results of this pooled study suggest

The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI.

Introduction: Antegrade nailing of proximal femur or femoral shaft fractures is a proven treatment with good to excellent results. Nonetheless, clinical evidence from Asia indicates that proximal femur nails can be too proud at the greater trochanter (GT) causing irritation for some Asian patients. This study aimed to identify any significant differences in proximal nail misfit for a set of Asian and Caucasian femora. Materials and methods: Two nails (Gamma3, TFNA) were virtually inserted into 63 femoral 3D models (28 Japanese, 4 Thai, 31 Caucasian). In AP, the entry point was 4° lateral for Gamma3 and 5° for TFNA; laterally the same location was used for both. Insertion depth was controlled by aligning the lag screw centre head. The distance of the nail end from the GT was measured at five (medial, lateral, anterior, posterior and centre) reference points (RPs). The correlation between GT height, CCD angle and proximal nail distance to GT was analysed. Results: There was no significant difference between either nail (p = 1.0). The TFNA was overall less prominent than the Gamma3, and significantly less prominent at all RPs except lateral. The Asian femora were 3.76 (p = 0.016) times more likely to have the nail protruding proximally. The Asian subjects were shorter (p < 0.05) than the Caucasians. Their GT height was slightly shorter and CCD angles larger compared to Caucasian (Asian: 41.1 mm, 128.1°, Caucasian: 42.2 mm, 126.4°), but the differences were not significant (p = 0.36). Stature, GT height and CCD angle significantly correlated with nail distance to GT. Conclusions: This study illustrated a significantly increased incidence of proximal nail protrusion in Asian compared to Caucasian femora, corroborating clinical findings. The combination of shorter stature and GT height and a larger CCD angle in Asians likely contributes to this difference.

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.

Cancer of the upper part of the esophagus occurs in 1 in 20 patients with esophageal cancer and is therefore a rare condition. The cornerstone of cancer treatment in general is surgical removal. However, in cancer of the upper part of the esophagus, surgery is no easy task and can be highly mutilating. This doctoral study examined the treatment options available to these patients and the outcomes they provide. It was determined that the risk of dying from this disease decreased, where in 1989-1994 only 1 in 20 patients were alive 5 years after diagnosis, this has increased to 1 in 8 patients in 2010-2014. This gain is mainly explained by the entry of combined treatment of chemotherapy and radiotherapy ("chemoradiation"). The survival of patients treated with surgery or chemoradiation was more or less the same. Because chemoradiation leads to less severe complications than surgery, the use of chemoradiation without surgery is currently the best treatment modality. It was also investigated which combination of chemotherapy and radiotherapy gave the best outcomes. It was concluded that the different regimens gave no difference in survival, but that carboplatin plus paclitaxel chemotherapy and low dose radiotherapy (≤50 Gy) resulted in fewer side effects.

The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI.

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.

Cancer of the upper part of the esophagus occurs in 1 in 20 patients with esophageal cancer and is therefore a rare condition. The cornerstone of cancer treatment in general is surgical removal. However, in cancer of the upper part of the esophagus, surgery is no easy task and can be highly mutilating. This doctoral study examined the treatment options available to these patients and the outcomes they provide. It was determined that the risk of dying from this disease decreased, where in 1989-1994 only 1 in 20 patients were alive 5 years after diagnosis, this has increased to 1 in 8 patients in 2010-2014. This gain is mainly explained by the entry of combined treatment of chemotherapy and radiotherapy ("chemoradiation"). The survival of patients treated with surgery or chemoradiation was more or less the same. Because chemoradiation leads to less severe complications than surgery, the use of chemoradiation without surgery is currently the best treatment modality. It was also investigated which combination of chemotherapy and radiotherapy gave the best outcomes. It was concluded that the different regimens gave no difference in survival, but that carboplatin plus paclitaxel chemotherapy and low dose radiotherapy (≤50 Gy) resulted in fewer side effects.

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.

BackgroundInterstitial fibrosis (IF) on kidney biopsy is one of the most potent risk factors for kidney disease progression. The furosemide stress test (FST) is a validated tool that predicts the severity of acute kidney injury (especially at 2 h) in critically ill patients. Since furosemide is secreted through the kidney tubules, the response to FST represents the tubular secretory capacity. To our knowledge there is no data on the correlation between functional tubular capacity assessed by the FST with IF on kidney biopsies from patients with chronic kidney disease (CKD). The aim of this study was to determine the association between urine output (UO), Furosemide Excreted Mass (FEM) and IF on kidney biopsies after a FST.MethodsThis study included 84 patients who underwent kidney biopsy for clinical indications and a FST. The percentage of fibrosis was determined by morphometry technique and reviewed by a nephropathologist. All patients underwent a FST prior to the biopsy. Urine volume and urinary sodium were measured in addition to urine concentrations of furosemide at different times (2, 4 and 6 h). We used an established equation to determine the FEM. Values were expressed as mean, standard deviation or percentage and Pearson Correlation.ResultsThe mean age of the participants was 38 years and 44% were male. The prevalence of diabetes mellitus, hypertension and diuretic use was significantly higher with more advanced degree of fibrosis. Nephrotic syndrome and acute kidney graft dysfunction were the most frequent indications for biopsy. eGFR was inversely related to the degree of fibrosis. Subjects with the highest degree of fibrosis (grade 3) showed a significant lower UO at first hour of the FST when compared to lower degrees of fibrosis (p = 0.015). Likewise, the total UO and the FEM was progressively lower with higher degrees of fibrosis. An inversely linear correlation between FEM and the degree of fibrosis (r = - 0.245, p = 0.02) was observed.ConclusionsOur

PURPOSE:The purpose of this study was to assess the effect on femoral torsion by rotational osteotomies at three different levels as measured in 3D using both the mechanical and the anatomic axes. METHODS:Ten cadaveric lower extremities underwent femoral osteotomies perpendicular to the anatomic axis (AA) at three levels: subtrochanteric, mid-diaphyseal and supracondylar. Parallel pins were placed, one in each femur segment. Computed tomography (CT) was acquired in post-osteotomies neutral position, then post-external rotation of the femur at each osteotomy level. Femurs were returned to neutral rotation between imaging exams. Using 3D CT reconstructions, custom software calculated femoral torsion (angle between the femoral neck axis and the posterior condylar axis in the transverse plane) and pin angle between segments, reoriented to both the mechanical axis (MA) and the AA. Pin angle and torsion change were compared for the three osteotomy locations (regression analysis and ANOVA performed). RESULTS:Two specimens were omitted (inadequate imaging); the remaining eight donors were 55-90 years old (mean: 64 ± 15 years), CT confirmed no bony defects. All three levels of osteotomy demonstrated significant correlations between the amount of rotation at the osteotomy (pin angle change) and the resulting change in femoral torsion (R square range 0.658-0.847). No significant differences were found between osteotomy level in torsion (MA:p = 0.285, AA:p = 0.156) or in pin angle (MA:p = 0.756, AA:p = 0.753). CONCLUSIONS:Performing a corrective rotational osteotomy orthogonal to the AA achieves the desired effect on MA regardless of location. This suggests that a surgeon's osteotomy level choice may be based on other risks/benefits of the various techniques.

BackgroundInterstitial fibrosis (IF) on kidney biopsy is one of the most potent risk factors for kidney disease progression. The furosemide stress test (FST) is a validated tool that predicts the severity of acute kidney injury (especially at 2 h) in critically ill patients. Since furosemide is secreted through the kidney tubules, the response to FST represents the tubular secretory capacity. To our knowledge there is no data on the correlation between functional tubular capacity assessed by the FST with IF on kidney biopsies from patients with chronic kidney disease (CKD). The aim of this study was to determine the association between urine output (UO), Furosemide Excreted Mass (FEM) and IF on kidney biopsies after a FST.MethodsThis study included 84 patients who underwent kidney biopsy for clinical indications and a FST. The percentage of fibrosis was determined by morphometry technique and reviewed by a nephropathologist. All patients underwent a FST prior to the biopsy. Urine volume and urinary sodium were measured in addition to urine concentrations of furosemide at different times (2, 4 and 6 h). We used an established equation to determine the FEM. Values were expressed as mean, standard deviation or percentage and Pearson Correlation.ResultsThe mean age of the participants was 38 years and 44% were male. The prevalence of diabetes mellitus, hypertension and diuretic use was significantly higher with more advanced degree of fibrosis. Nephrotic syndrome and acute kidney graft dysfunction were the most frequent indications for biopsy. eGFR was inversely related to the degree of fibrosis. Subjects with the highest degree of fibrosis (grade 3) showed a significant lower UO at first hour of the FST when compared to lower degrees of fibrosis (p = 0.015). Likewise, the total UO and the FEM was progressively lower with higher degrees of fibrosis. An inversely linear correlation between FEM and the degree of fibrosis (r = - 0.245, p = 0.02) was observed.ConclusionsOur

PURPOSE:The purpose of this study was to assess the effect on femoral torsion by rotational osteotomies at three different levels as measured in 3D using both the mechanical and the anatomic axes. METHODS:Ten cadaveric lower extremities underwent femoral osteotomies perpendicular to the anatomic axis (AA) at three levels: subtrochanteric, mid-diaphyseal and supracondylar. Parallel pins were placed, one in each femur segment. Computed tomography (CT) was acquired in post-osteotomies neutral position, then post-external rotation of the femur at each osteotomy level. Femurs were returned to neutral rotation between imaging exams. Using 3D CT reconstructions, custom software calculated femoral torsion (angle between the femoral neck axis and the posterior condylar axis in the transverse plane) and pin angle between segments, reoriented to both the mechanical axis (MA) and the AA. Pin angle and torsion change were compared for the three osteotomy locations (regression analysis and ANOVA performed). RESULTS:Two specimens were omitted (inadequate imaging); the remaining eight donors were 55-90 years old (mean: 64 ± 15 years), CT confirmed no bony defects. All three levels of osteotomy demonstrated significant correlations between the amount of rotation at the osteotomy (pin angle change) and the resulting change in femoral torsion (R square range 0.658-0.847). No significant differences were found between osteotomy level in torsion (MA:p = 0.285, AA:p = 0.156) or in pin angle (MA:p = 0.756, AA:p = 0.753). CONCLUSIONS:Performing a corrective rotational osteotomy orthogonal to the AA achieves the desired effect on MA regardless of location. This suggests that a surgeon's osteotomy level choice may be based on other risks/benefits of the various techniques.

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.

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.

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.

The concentration of glucose in plasma is held within narrow limits (4-10 mmol/l), primarily to ensure fuel supply to the brain. Kidneys play a role in glucose homeostasis in the body by ensuring that glucose is not lost in the urine. Three membrane proteins are responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule: sodium-glucose cotransporters SGLT1 and SGLT2, in the apical membrane, and GLUT2, a uniporter in the basolateral membrane. 'Knockout' of these transporters in mice and men results in the excretion of filtered glucose in the urine. In humans, intravenous injection of the plant glucoside phlorizin also results in excretion of the full filtered glucose load. This outcome and the finding that, in an animal model, phlorizin reversed the symptoms of diabetes, has stimulated the development and successful introduction of SGLT2 inhibitors, gliflozins, in the treatment of type 2 diabetes mellitus. Here we summarise the current state of our knowledge about the physiology of renal glucose handling and provide background to the development of SGLT2 inhibitors for type 2 diabetes treatment.

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.

Accurate determination of age is important in the legal process; when a person’s age is unknown or must be authenticated, a forensic age identification method must be applied. One of such methods is to assess the epiphyseal closure on the bone through radiological examination. The main problem associated with the use of this method is the relevance of the reference population provided because epiphyseal closure is influenced by genetics and nutrition. This method needs data to represent each population. Radiological examination of elbow bones of 30 male patients aged 11-30 years and 18 female patients aged 14-28 years in Dr. Soetomo Hospital, Surabaya from January to April 2016 was carried out to determine the time of epiphyseal closure of the radius and ulna distal section. This was cross-sectional descriptive study. In conclusion, epiphyseal closure of proximal radius and ulna is complete at age 16 in males and 14 in females.

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.

The concentration of glucose in plasma is held within narrow limits (4-10 mmol/l), primarily to ensure fuel supply to the brain. Kidneys play a role in glucose homeostasis in the body by ensuring that glucose is not lost in the urine. Three membrane proteins are responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule: sodium-glucose cotransporters SGLT1 and SGLT2, in the apical membrane, and GLUT2, a uniporter in the basolateral membrane. 'Knockout' of these transporters in mice and men results in the excretion of filtered glucose in the urine. In humans, intravenous injection of the plant glucoside phlorizin also results in excretion of the full filtered glucose load. This outcome and the finding that, in an animal model, phlorizin reversed the symptoms of diabetes, has stimulated the development and successful introduction of SGLT2 inhibitors, gliflozins, in the treatment of type 2 diabetes mellitus. Here we summarise the current state of our knowledge about the physiology of renal glucose handling and provide background to the development of SGLT2 inhibitors for type 2 diabetes treatment.

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.

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 tubular epithelial cells subjected to fluid shear stress by culturing the cells on an orbital shaker. Transepithelial electrical resistance (TEER), 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 TEER, 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.

Accurate determination of age is important in the legal process; when a person’s age is unknown or must be authenticated, a forensic age identification method must be applied. One of such methods is to assess the epiphyseal closure on the bone through radiological examination. The main problem associated with the use of this method is the relevance of the reference population provided because epiphyseal closure is influenced by genetics and nutrition. This method needs data to represent each population. Radiological examination of elbow bones of 30 male patients aged 11-30 years and 18 female patients aged 14-28 years in Dr. Soetomo Hospital, Surabaya from January to April 2016 was carried out to determine the time of epiphyseal closure of the radius and ulna distal section. This was cross-sectional descriptive study. In conclusion, epiphyseal closure of proximal radius and ulna is complete at age 16 in males and 14 in females.

Accurate determination of age is important in the legal process; when a person’s age is unknown or must be authenticated, a forensic age identification method must be applied. One of such methods is to assess the epiphyseal closure on the bone through radiological examination. The main problem associated with the use of this method is the relevance of the reference population provided because epiphyseal closure is influenced by genetics and nutrition. This method needs data to represent each population. Radiological examination of elbow bones of 30 male patients aged 11-30 years and 18 female patients aged 14-28 years in Dr. Soetomo Hospital, Surabaya from January to April 2016 was carried out to determine the time of epiphyseal closure of the radius and ulna distal section. This was cross-sectional descriptive study. In conclusion, epiphyseal closure of proximal radius and ulna is complete at age 16 in males and 14 in females.

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.

In vitro data indicates that the kidney proximal tubule (PT) transporters of uremic toxins and solutes (e.g., indoxyl sulfate, p-cresol sulfate, kynurenine, creatinine, urate) include two "drug" transporters of the organic anion transporter (OAT) family: OAT1 (SLC22A6, originally NKT) and OAT3 (SLC22A8). Here, we have examined new and prior metabolomics data from the Oat1KO and Oat3KO, as well as newly obtained metabolomics data from a "chemical double" knockout (Oat3KO plus probenecid). This gives a picture of the in vivo roles of OAT1 and OAT3 in the regulation of the uremic solutes and supports the centrality of these "drug" transporters in independently and synergistically regulating uremic metabolism. We demonstrate a key in vivo role for OAT1 and/or OAT3 in the handling of over 35 uremic toxins and solutes, including those derived from the gut microbiome (e.g., CMPF, phenylsulfate, indole-3-acetic acid). Although it is not clear whether trimethylamine-N-oxide (TMAO) is directly transported, the Oat3KO had elevated plasma levels of TMAO, which is associated with cardiovascular morbidity in chronic kidney disease (CKD). As described in the Remote Sensing and Signaling (RSS) Hypothesis, many of these molecules are involved in interorgan and interorganismal communication, suggesting that uremia is, at least in part, a disorder of RSS.

In vitro data indicates that the kidney proximal tubule (PT) transporters of uremic toxins and solutes (e.g., indoxyl sulfate, p-cresol sulfate, kynurenine, creatinine, urate) include two "drug" transporters of the organic anion transporter (OAT) family: OAT1 (SLC22A6, originally NKT) and OAT3 (SLC22A8). Here, we have examined new and prior metabolomics data from the Oat1KO and Oat3KO, as well as newly obtained metabolomics data from a "chemical double" knockout (Oat3KO plus probenecid). This gives a picture of the in vivo roles of OAT1 and OAT3 in the regulation of the uremic solutes and supports the centrality of these "drug" transporters in independently and synergistically regulating uremic metabolism. We demonstrate a key in vivo role for OAT1 and/or OAT3 in the handling of over 35 uremic toxins and solutes, including those derived from the gut microbiome (e.g., CMPF, phenylsulfate, indole-3-acetic acid). Although it is not clear whether trimethylamine-N-oxide (TMAO) is directly transported, the Oat3KO had elevated plasma levels of TMAO, which is associated with cardiovascular morbidity in chronic kidney disease (CKD). As described in the Remote Sensing and Signaling (RSS) Hypothesis, many of these molecules are involved in interorgan and interorganismal communication, suggesting that uremia is, at least in part, a disorder of RSS.

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.

BackgroundProximal tubular dysfunction (PTD) is common in HIV-positive persons and has been associated with tenofovir disoproxil fumarate (TDF). However, few studies have assessed the natural history PTD in HIV-positive and -negative individuals, or the association of PTD with the subsequent trajectory of directly measured glomerular filtration rate (mGFR).MethodsWe followed 192 HIV-positive and 100 HIV-negative, nondiabetic participants for 3 years. We measured 3 PTD markers (normoglycemic glycosuria, fractional excretion of phosphorus, and tubular proteinuria) and mGFR (by iohexol disappearance from serum) annually. We used univariate and multivariate generalized estimating equation logistic regression to identify factors associated with PTD across all visits and linear mixed effects models to assess the association between baseline PTD and mGFR slope.ResultsCompared with HIV-negative participants, HIV-positive persons that were not taking antiretroviral therapy were at increased risk of PTD (adjusted odds ratio 3.33; 95% confidence interval: 1.65 to 6.71), whereas those taking a TDF-based or a TDF-sparing regimen were not at significantly increased risk of PTD. Among HIV-positive participants, uncontrolled viremia was a strong correlate of PTD. Forty-nine of 55 (89%) participants with PTD at baseline had at least 1 subsequent visit without PTD. There was no association between baseline PTD and rate of decline in mGFR over time.ConclusionsPoorly controlled HIV may be a stronger risk factor for PTD than TDF use. The individual-level variability of the PTD markers over time was high, potentially limiting their usefulness for routine screening in unselected patients. Baseline PTD was not associated with subsequent mGFR slope.

Coenzyme Q (Q) is a lipid-soluble antioxidant essential in cellular physiology. Patients with Q deficiencies, with few exceptions, seldom respond to treatment. Current therapies rely on dietary supplementation with Q10, but due to its highly lipophilic nature, Q10 is difficult to absorb by tissues and cells. Plant polyphenols, present in the human diet, are redox active and modulate numerous cellular pathways. In the present study, we tested whether treatment with polyphenols affected the content or biosynthesis of Q. Mouse kidney proximal tubule epithelial (Tkpts) cells and human embryonic kidney cells 293 (HEK 293) were treated with several types of polyphenols, and kaempferol produced the largest increase in Q levels. Experiments with stable isotope 13C-labeled kaempferol demonstrated a previously unrecognized role of kaempferol as an aromatic ring precursor in Q biosynthesis. Investigations of the structure-function relationship of related flavonols showed the importance of two hydroxyl groups, located at C3 of the C ring and C4' of the B ring, both present in kaempferol, as important determinants of kaempferol as a Q biosynthetic precursor. Concurrently, through a mechanism not related to the enhancement of Q biosynthesis, kaempferol also augmented mitochondrial localization of Sirt3. The role of kaempferol as a precursor that increases Q levels, combined with its ability to upregulate Sirt3, identify kaempferol as a potential candidate in the design of interventions aimed on increasing endogenous Q biosynthesis, particularly in kidney.

The research examined the individual and collective influence of ‘Indigenous status’ and ‘remoteness’ on road crash profiles. Interviews with 229 crash patients recruited through health facilities in North Queensland showed that involvement of unsafe behaviours in crashes increased with remoteness, and were more marked among Indigenous patients (proximal causation). Themes identified as influencing behaviour included social acceptance of risk (‘rural way of life’), bravado among young males and feelings of hopelessness among the Indigenous sample (distal causation). Using this knowledge, recommendations are provided under the ‘Safe System’ framework with a particular focus on improving Indigenous program development and delivery.

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.

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).

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.

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.

Syfte: Att enbart jämföra klinisk undersökning med klinisk undersökning i kombination med bitewingundersökning avseende initial och manifest approximalkaries på premolarer och molarer hos 15-åriga barn i Da Nang, Vietnam. Metod och material: En tvärsnittsstudie. Röntgenbilder har använts som material i denna studie. Studien bygger delvis på kliniskt insamlat material från en randomiserad epidemiologisk studie. Studien bestod av sammanlagt 200 slumpmässigt utvalda 15-åriga deltagare. Undersökningen bestod av fyra röntgenbilder med bitewingteknik. Studien fokuserar på mesiala och distala ytor på premolarer och molarer. Resultat: Vid jämförelse av klinisk undersökning med bitewingundersökning hittades ytterligare 152 approximala initiala kariesangrepp respektive 71 approximala manifesta kariesangrepp vid bitewingundersökningen. Total kariesprevalens på molarer och premolarers alla ytor visar ett medelvärde för initialkaries på 2,1 ytor per barn och vid manifest karies ett medelvärde på 4,6 ytor per barn vid klinisk undersökning i kombination med bitewing. Karies förekom oftast på bettets första molarer vid klinisk undersökning och bitewingundersökning. En statistisk signifikant skillnad, p-värde <0,001 fanns mellan klinisk undersökning och klinisk undersökning i kombination med bitewingundersökning av approximal initial och manifest karies. Slutsatser: En kombinerad undersökningsstrategi (klinisk undersökning och bitewingundersökning) är säkrare som metod vid undersökning av initial och manifest approximal karies., Title: The importance of radiographic examination (bitewing) combined with clinical examination of 15-year old children in Da Nang, Vietnam. Aim: Comparing only clinical examination with clinical examination combined with radiographic examination (bitewing) in initial and manifest proximal caries on premolars and molars of 15-year-old children in Da Nang, Vietnam. Methods: A cross-sectional study. X-ray images were used as material in this study. This study includes partly data from a randomized epidemiological study. The subjects were 200 children, 15 years old. A set of standard posterior bitewing radiographs was taken. Two surfaces (mesial and distal approximal surfaces) of premolars and molars were noted and recorded. Results: On comparing clinical examination findings with radiographic examination, radiographic examination found an additional 154 approximal initial surfaces and 71 approximal manifest surfaces that were not evident clinically. Caries prevalence of molars and premolars on all surfaces with clinical examination combined with radiographic examination showed a mean value of 6,8 decayed surfaces per child. The proximal surfaces most often affected by caries at the radiographic and clinical examination were the first molars. A statistically significant difference, p-value < 0,001 was when comparing the clinical examination alone and clinical examination combined with radiographic examination of proximal initial and manifest caries lesions. Conclusions: The use of bitewing radiographs combined with careful clinical examination is of great advantage in detection of proximal initial and manifest caries of premolars and molars in children.

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.

Syfte: Att enbart jämföra klinisk undersökning med klinisk undersökning i kombination med bitewingundersökning avseende initial och manifest approximalkaries på premolarer och molarer hos 15-åriga barn i Da Nang, Vietnam. Metod och material: En tvärsnittsstudie. Röntgenbilder har använts som material i denna studie. Studien bygger delvis på kliniskt insamlat material från en randomiserad epidemiologisk studie. Studien bestod av sammanlagt 200 slumpmässigt utvalda 15-åriga deltagare. Undersökningen bestod av fyra röntgenbilder med bitewingteknik. Studien fokuserar på mesiala och distala ytor på premolarer och molarer. Resultat: Vid jämförelse av klinisk undersökning med bitewingundersökning hittades ytterligare 152 approximala initiala kariesangrepp respektive 71 approximala manifesta kariesangrepp vid bitewingundersökningen. Total kariesprevalens på molarer och premolarers alla ytor visar ett medelvärde för initialkaries på 2,1 ytor per barn och vid manifest karies ett medelvärde på 4,6 ytor per barn vid klinisk undersökning i kombination med bitewing. Karies förekom oftast på bettets första molarer vid klinisk undersökning och bitewingundersökning. En statistisk signifikant skillnad, p-värde <0,001 fanns mellan klinisk undersökning och klinisk undersökning i kombination med bitewingundersökning av approximal initial och manifest karies. Slutsatser: En kombinerad undersökningsstrategi (klinisk undersökning och bitewingundersökning) är säkrare som metod vid undersökning av initial och manifest approximal karies., Title: The importance of radiographic examination (bitewing) combined with clinical examination of 15-year old children in Da Nang, Vietnam. Aim: Comparing only clinical examination with clinical examination combined with radiographic examination (bitewing) in initial and manifest proximal caries on premolars and molars of 15-year-old children in Da Nang, Vietnam. Methods: A cross-sectional study. X-ray images were used as material in this study. This study includes partly data from a randomized epidemiological study. The subjects were 200 children, 15 years old. A set of standard posterior bitewing radiographs was taken. Two surfaces (mesial and distal approximal surfaces) of premolars and molars were noted and recorded. Results: On comparing clinical examination findings with radiographic examination, radiographic examination found an additional 154 approximal initial surfaces and 71 approximal manifest surfaces that were not evident clinically. Caries prevalence of molars and premolars on all surfaces with clinical examination combined with radiographic examination showed a mean value of 6,8 decayed surfaces per child. The proximal surfaces most often affected by caries at the radiographic and clinical examination were the first molars. A statistically significant difference, p-value < 0,001 was when comparing the clinical examination alone and clinical examination combined with radiographic examination of proximal initial and manifest caries lesions. Conclusions: The use of bitewing radiographs combined with careful clinical examination is of great advantage in detection of proximal initial and manifest caries of premolars and molars in children.

Urinary citrate is an important inhibitor of calcium-stone formation. Most of the citrate reabsorption in the proximal tubule is thought to occur via a dicarboxylate transporter NaDC1 located in the apical membrane. OK cells, an established opossum kidney proximal tubule cell line, transport citrate but the characteristics change with extracellular calcium such that low calcium solutions stimulate total citrate transport as well as increase the apparent affinity for transport. The present studies address several fundamental properties of this novel process: the polarity of the transport process, the location of the calcium-sensitivity and whether NaDC1 is present in OK cells. OK cells grown on permeable supports exhibited apical >basolateral citrate transport. Apical transport of both citrate and succinate was sensitive to extracellular calcium whereas basolateral transport was not. Apical calcium, rather than basolateral, was the predominant determinant of changes in transport. Also 2,3-dimethylsuccinate, previously identified as an inhibitor of basolateral dicarboxylate transport, inhibited apical citrate uptake. Although the calcium-sensitive transport process in OK cells is functionally not typical NaDC1, NaDC1 is present in OK cells by Western blot and PCR. By immunolocalization studies, NaDC1 was predominantly located in discrete apical membrane or subapical areas. However, by biotinylation, apical NaDC1 decreases in the apical membrane with lowering calcium. In sum, OK cells express a calcium-sensitive/regulated dicarboxylate process at the apical membrane which responds to variations in apical calcium. Despite the functional differences of this process compared to NaDC1, NaDC1 is present in these cells, but predominantly in subapical vesicles.