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Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson’s marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.

Background and purpose: Cancer is the leading cause of death in today’s world, therefore the efforts to achieve anticancer drugs with higher potency and fewer side effects have always been conducted by researchers in the field of pharmaceutical chemistry. Monastrol, a cytotoxic small molecule, from dihydropyrimidinone scaffold, is an inhibitor of the kinesin-5 protein. So, efforts to identify more derivatives of this molecule have been of interest. Experimental approach: Some of monastrol’s analogs as Eg5 inhibitors with different substitution patterns were analyzed, synthesized, and their cytotoxic effects were evaluated on MCF-7 and HeLa cancerous cells in vitro using the MTT assay. The structure-activity relationship (SAR) was studied in silico by molecular docking. Findings / Results: Among all proposed structures, in ducking study, those with hydrophobic moieties on the C2-N3 region, those with a hydroxyl group on the phenyl on C4 position, and those with a carboxylic group on C5 were the best candidates. In vitro studies, on the other side, emphasized that monastrol still was the most potent derivative. Another finding was the more moderate activity of synthesized compounds on the HeLa cell compared to the MCF-7 cell line. During different challenges for substitution at 5-position, some earlier reports around the dihydropyrimidinone reactions were questioned. It seems that the change at the position 5 is not merely accessible, as earlier reports claimed. Also, we could not achieve any better cell cytotoxicity by the larger group in the thiourea region or position 5; nonetheless, it seems that the introduction of a methylene group at this position could be beneficial. Conclusion and implications: The initial results of this study were valuable in terms of design and synthesis and will be useful for future investigations.

Ulcers including pressure ulcers and diabetic foot ulcers damage the skin and underlying tissue in people with compromised blood circulation. They are classified into four stages of severity and span from mild reddening of the skin to tissue damage and muscle/bone infections. Here, we used photoacoustic imaging as a noninvasive method for detecting early tissue damage that cannot be visually observed while also staging the disease using quantitative image analysis. We used a mouse model of pressure ulcers by implanting subdermal magnets in the dorsal flank and periodically applying an external magnet to the healed implant site. The magnet-induced pressure was applied in cycles, and the extent of ulceration was dictated by the number of cycles. We used both laser- and light-emitting diode (LED)-based photoacoustic imaging tools with 690 nm excitation to evaluate the change in photoacoustic signal and depth of injury. Using laser-based photoacoustic imaging system, we found a 4.4-fold increase in the photoacoustic intensity in stage I vs. baseline (no pressure). We also evaluated the depth of injury using photoacoustics. We measured a photoacoustic ulcer depth of 0.38 ± 0.09 mm, 0.74 ± 0.11 mm, 1.63 ± 0.4 mm, and 2.7 ± 0.31 mm (n = 4) for stages I–IV, respectively. The photoacoustic depth differences between each stage were significant (p < 0.05). We also used an LED-based photoacoustic imaging system to detect early stage (stage I) pressure ulcers and observed a 2.5-fold increase in photoacoustic signal. Importantly, we confirmed the capacity of this technique to detect dysregulated skin even before stage I ulcers have erupted. We also observed significant changes in photoacoustic intensity during healing suggesting that this approach can monitor therapy. These findings were confirmed with histology. These results suggest that this photoacoustic-based approach might have clinical value for monitoring skin diseases including pressure ulcers.

Background and Aims Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) experience various symptoms due to increasing kidney volume and its associated complications. To understand symptom burden, qualitative interviews were conducted to characterize the ADPKD patient experience pertaining to the most common and disturbing symptoms. Method Combined concept elicitation and cognitive debriefing interviews were performed by trained interviewers following a preliminary conceptual model based on a targeted literature review. We currently report on the concept elicitation component, which explored relevant and bothersome symptoms in ADPKD patients, due to either the disease or associated treatments. Nineteen telephone interviews were conducted in four waves of 5, 4, 6, and 4 patients, respectively. Results The mean age of patients was 47 years (SD: 9 years); 68% (n=13) were female, and the mean estimated glomerular filtration rate (eGFR) was 41 ml/min/1.73m2 (SD: 25 ml/min/1.73m2), with the majority 47% (n=9) in stage 3 chronic kidney disease (CKD). The classes of treatments included antihypertensives (74%, n=14), vasopressin receptor antagonists (21%, n=4); diuretics (16%, n=3), analgesics (16%, n=3) and erythropoietin (5%, n=1). The most frequently mentioned symptoms were fatigue (89%, n=17), pain (84%, n=16), and nocturia (74%, n=14); all were considered at least moderately disturbing to patients’ lives. Most patients experienced constant fatigue (74%, n=14) that worsened over time. Patients’ descriptions of pain were variable, including back and side pain, severe cystic pain, and muscle pain; a few patients also mentioned shoulder pain, or pain due to kidney stones. Among patients reporting nocturia (n=14), about half (57%, n=8) rated nocturia on the upper end of the disturbance scale, regardless of number of voids per night, often accompanied by sleep disruption. While less frequently occurring, itchy skin, muscle cramping, abdominal swelling, and inability to eat were spontaneously mentioned among the most disturbing symptoms. Conclusion The novel component of this study is the significant disruption of nocturia in patients with ADPKD even in the absence of vasopressin receptor antagonist administration. In addition, it confirms the findings of the literature review and highlights the patient experience in ADPKD, most notably fatigue, nocturia, and pain as the most frequent and bothersome symptoms experienced by patients. Subjective evaluation of the ADPKD patient experience is critical to understand symptom severity and the burden of disease, to potentially quantify disease progression, and to assess the impact of emerging therapies.

Heparin is an indispensable drug in anticoagulation therapy but with a narrow therapeutic window, which dictates regular testing and dose adjustment. However, current monitoring tools have a long turnaround time or are operator intensive. In this work, we describe a cellulose-based photoacoustic sensor for heparin. The sensors have a turnaround time of 6 min for whole blood samples and 3 min for plasma samples regardless of heparin concentration. These sensors have a limit of detection of 0.28 U/ml heparin in human plasma and 0.29 U/ml in whole blood with a linear response (Pearson's r = 0.99) from 0 to 2 U/ml heparin in plasma and blood samples. The relative standard deviation was

In this paper, we show that gadolinium-loaded synthetic melanin nanoparticles (Gd(III)-SMNPs) exhibit up to a 40-fold enhanced photoacoustic signal intensity relative to synthetic melanin alone and higher than other metal-chelated SMNPs. This property makes these materials useful as dual labeling agents because Gd(III)-SMNPs also behave as magnetic resonance imaging (MRI) contrast agents. As a proof-of-concept, we used these nanoparticles to label human mesenchymal stem cells. Cellular uptake was confirmed with bright-field optical and transmission electron microscopy. The Gd(III)-SMNP-labeled stem cells continued to express the stem cell surface markers CD73, CD90, and CD105 and proliferate. The labeled stem cells were subsequently injected intramyocardially in mice, and the tissue was observed by photoacoustic and MR imaging. We found that the photoacoustic signal increased as the cell number increased (R(2) = 0.96), indicating that such an approach could be employed to discriminate between stem cell populations with a limit of detection of 2.3 × 10(4) cells in in vitro tests. This multimodal photoacoustic/MRI approach combines the excellent temporal resolution of photoacoustics with the anatomic resolution of MRI.

We recently reported a real-time method to measure heparin in human whole blood based on the photoacoustic change of methylene blue (MB). Intriguingly, the MB behaved unlike other "turn on" photoacoustic probes-the absorbance decreased as the photoacoustic signal increased. The underlying mechanism was not clear and motivated this study. We studied the binding mechanism of MB and heparin in water and phosphate buffer saline (PBS) with both experimental and computational methods. We found that the photoacoustic enhancement of the MB-heparin mixture was a result of MB-heparin aggregation due to charge neutralization and resulting sequestration of MB in these aggregates. The sequestration of MB in the MB-heparin aggregates led to decreased absorbance-there was simply less free dye in solution to absorb light. The highest photoacoustic signal and aggregation occurred when the number of negatively charged sulfate groups on heparin was approximately equal to the number of positively charged MB molecule. The MB-heparin aggregates dissociated when there were more sulfated groups from heparin than MB molecules because of the electrostatic repulsion between negatively charged sulfate groups. PBS facilitated MB dimer formation regardless of heparin concentration and reprecipitated free MB in aggregates due to ionic strength and ionic shielding. Further molecular dynamics experiments found that binding of heparin occurred at the sulfates and glucosamines in heparin. Phosphate ions could interact with the heparin via sodium ions to impair the MB-heparin binding. Finally, our model found 3.7-fold more MB dimerization upon addition of heparin in MB solution confirming that heparin facilitates MB aggregation. We conclude that the addition of heparin in MB decreases the absorbance of the sample because of MB-heparin aggregation leading to fewer MB molecules in solution; however, the aggregation also increases the PA intensity because the MB molecules in the MB-heparin aggregate have reduced degrees of freedom and poor heat transfer to solvent.

Background:To assess cardiovascular risk among various hemoglobin (Hb) rates of rise (RoR) in chronic kidney disease (CKD) patients with anemia who have initiated therapy with erythropoiesis stimulating agents (ESAs).Methods:Observational cohort of CKD patients initiating ESA therapy from the Centricity®database, 1990–2011. Proportional hazards models tested the hypothesis that a slower Hb RoR (0 < g/dl/month ⩽ 0.125) is associated with a lower cardiovascular (CV) incidence [composite of fatal/nonfatal myocardial infarction (MI) and stroke] compared with faster RoR (0.125 < g/dl/month ⩽ 2.0, and >2.0 g/dl/month).Results:A total of 9220 patients receiving ESAs were followed for an average of 3.1 years. Slow (group B) RoR versus medium (group C′) and fast (group D′) RoR in Hb, throughout all Hb milestones, was associated with lower risk of the composite endpoint [B (slow) versus D′ (fast) [hazard ratio (HR) = 0.20 (0.11, 0.39), p < 0.0001]; B versus C′ (medium) [HR = 0.34 (0.19, 0.62), p = 0.0004], and C′ versus D′ [HR = 0.60 (0.42, 0.85), p = 0.005]]. Within achieved Hb milestones, HRs were: B versus D′ at milestone ⩾ 14.1 g/dl [HR = 0.17 (0.05, 0.56); p = 0.004] and at milestone 12.6−14.0 [HR = 0.18 (0.07, 0.46), p = 0.0004].Conclusion:Rapid Hb rise is associated with adverse CV outcomes, with markedly lower risk for rates below a threshold trajectory of 0.125 g/dl/month, even with complete correction.

Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases.

Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and—most critically—patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.

We developed and designed a near-infrared (NIR) absorbing diboronate xanthene dye ((E)-1,3,3-trimethyl-2-(2-(6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-2,3-dihydro-1H-xanthen-4-yl)vinyl)-3H-indol-1-ium) for photoacoustic imaging that is sensitive to reactive oxygen and nitrogen species (RONS). We initially used the probe with an OPO-based laser but found that the photoacoustic intensity degrades by 2.6-fold within 3150 laser pulses. Therefore, we adopted the probe to a LED-based excitation source (The average and standard deviation of photoacoustic intensity in presence of 3150 LED pulses is 118.08 and 1.67 (1.4% variation) respectively) and found that hydrogen peroxide (H2O2), superoxide radical (O2˙ −), and peroxynitrite (ONOO−) produce absorption at 700 nm, which was used for photoacoustic excitation. We observed a photoacoustic intensity increase of 2.1-, 1.9-, and 1.75-fold with addition of ONOO−, O2˙ −, and H2O2, (50 ), respectively. The dye is not sensitive to OCl − and ˙OH. At vascular compartment, formation of ONOO− is based on the reaction of nitric oxide (˙NO) with superoxide radical (O2˙ −) and formed ONOO− xidize plasmatic components as well as reaction with intracellular. We then tested the photoacoustic response of various concentrations of ONOO− (25, 50, 125, 185, 250, 375, and 500) in whole human plasma and blood. Concentrations of 50 ONOO− were also easily detectable with this probe. Finally, we examined the capability of new molecular probe for detection of endogenous RONS via SKOV3 (ovarian cancer) cell media. The RONS from these cells activated the probe but media treated with N-acetylcystein (NAC) (RONS scavenger) did not. In pre-incubated cells with NAC, we observed 2.5-fold decrease in photoacoustic intensity versus untreated cells.

Follicular unit extraction (FUE) and follicular unit transplantation (FUT) account for 99% of hair transplant procedures. In both cases, it is important for clinicians to characterize follicle density for treatment planning and evaluation. The existing gold-standard is photographic examination. However, this approach is insensitive to subdermal hair and cannot identify follicle orientation. Here, we introduce a fast and non-invasive imaging technique to measure follicle density and angles across regions of varying density. We first showed that hair is a significant source of photoacoustic signal. We then selected regions of low, medium, and high follicle density and showed that photoacoustic imaging can measure the density of follicles even when they are not visible by eye. We performed handheld imaging by sweeping the transducer across the imaging area to generate 3D images via maximum intensity projection. Background signal from the dermis was removed using a skin tracing method. Measurement of follicle density using photoacoustic imaging was highly correlated with photographic determination (R2 = 0.96). Finally, we measured subdermal follicular angles—a key parameter influencing transection rates in FUE.

LED-based photoacoustic imaging has practical value in that it is affordable and rugged; however, this technology has largely been confined to anatomic imaging with limited applications into functional or molecular imaging. Here, we report molecular imaging reactive oxygen and nitrogen species (RONS) with a near-infrared (NIR) absorbing small molecule (CyBA) and LED-based photoacoustic imaging equipment. CyBA produces increasing photoacoustic signal in response to peroxynitrite (ONOO−) and hydrogen peroxide (H2O2) with photoacoustic signal increases of 3.54 and 4.23-fold at 50 µM of RONS at 700 nm, respectively. CyBA is insensitive to OCl−, ˙NO, NO2−, NO3−, tBuOOH, O2−, C4H9O˙, HNO, and ˙OH, but can detect ONOO− in whole blood and plasma. CyBA was then used to detect endogenous RONS in macrophage RAW 246.7 cells as well as a rodent model; these results were confirmed with fluorescence microscopy. Importantly, CyB suffers photobleaching under a Nd:YAG laser but the signal decrease is

The gold-standard periodontal probe is an aging tool that can detect periodontitis and monitor gingival health but is highly error-prone, does not fully characterize the periodontal pocket, and causes pain. Photoacoustic imaging is a noninvasive technique that can address these limitations. Here, a range of ultrasound frequencies between 16–40 MHz were used to image the periodontium and a contrast medium based on cuttlefish ink was used to label the pockets. A 40 MHz ultrasound frequency could spatially resolve the periodontal anatomy, including tooth, gum, gingival margin, and gingival thickness of tooth numbers 7–10 and 22–27. The photoacoustic-ultrasound measurements were more precise (0.01 mm) than those taken with physical probes by a dental hygienist. Furthermore, the full geometry of the pockets could be visualized with relative standard deviations of 10% (n = 5). This study shows the potential for non-invasive monitoring of periodontal health with photoacoustic-ultrasound imaging in the dental clinic. Keywords: Photoacoustic imaging, Periodontal disease, Diagnosis, Gingival thickness, Pocket depth, Periodontal charting, Melanin nanoparticles

Periodontal probing is a useful diagnostic tool to estimate the periodontal pocket depth and assess the status of periodontal disease, but is limited by systematic and random errors. Here, we used photoacoustic imaging in tandem with a food grade cuttlefish ink contrast agent to specifically measure pocket depths in swine models (n=27 teeth) and then compared this to Williams probe. Photoacoustic imaging used a Vevo LAZR imaging system (Visualsonics) at 40 MHz. Spectral data was collected at both 680 and 800 nm to discriminate between the photoacoustic signal from stains and contrast agent. The pocket depths were measured on the sagittal view of the 3D images as well as with a Williams probe before photoacoustic imaging. The Bland-Altman plots show that 97% of our samples fell within ± 1.96 standard deviations of the differences between the depths measured by photoacoustic imaging and the probe (95% confidence interval) at mesial, lingual and buccal, and distal locations. Small bias values of -0.04, +0.17, and -0.2 mm were identified at mesial, lingual and buccal, and distal locations, respectively; the 95% confidence intervals are plotted as well and all are < 1.0 mm. The photoacoustic imaging approach also offered 0.01 mm precision and could cover the entire pocket versus the probe-based approach that is limited to only a few sites.

Stem cell therapy has the potential to improve tissue remodeling and repair. For cardiac stem cell therapy, methods to improve the injection and tracking of stem cells may help to increase patient outcomes. Here we describe a multimodal approach that combines ultrasound imaging, photoacoustic imaging, and magnetic particle imaging (MPI). Ultrasound imaging offers real-time guidance, photoacoustic imaging offers enhanced contrast, and MPI offers high-contrast, deep-tissue imaging. This work was facilitated by a poly(lactic-co-glycolic acid) (PLGA)-based iron oxide nanobubble labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR) as a trimodal contrast agent. The PLGA coating facilitated the ultrasound signal, the DiR increased the photoacoustic signal, and the iron oxide facilitated the MPI signal. We confirmed that cell metabolism, proliferation, differentiation, and migration were not adversely affected by cell treatment with nanobubbles. The nanobubble-labeled cells were injected intramyocardially into live mice for real-time imaging. Ultrasound imaging showed a 3.8-fold increase in the imaging intensity of labeled cells postinjection compared to the baseline; photoacoustic imaging showed a 10.2-fold increase in the cardiac tissue signal postinjection. The MPI intensity of the nanobubble-treated human mesenchymal stem cells injected into the hearts of mice was approximately 20-fold greater than the negative control.

Photoacoustic imaging (PAI) has proved to be a promising non-invasive technique for diagnosis, prognosis and treatment monitoring of neurological disorders in small and large animals. Skull bone effects both light illumination and ultrasound propagation. Hence, the PA signal is largely affected. This study aims to quantify and compare the attenuation of PA signal due to the skull obstacle in the light illumination path, in the ultrasound propagation path, or in both. The effect of mouse, rat, and mesocephalic dog skull bones, ex-vivo, is quantitatively studied.

There is a need for continued research into the diagnosis, prevention and cure of neonatal brain disease and disorders. These disorders lead to fatalities and developmental disorders in infants. Non-invasive imaging techniques are being researched for this purpose. However, the availability of neonatal skull samples for this work is very low. A phantom can be used to simulate the neonatal skull and brain to improve imaging techniques. This study selects a phantom of polyurethane and titanium dioxide and proves its value as a replacement for neonatal skull in research. The methods used for this proof are validation of choice against the literature, transmissivity and acoustic experimentation compared to existing literature, and finally photoacoustic evaluation of the final choice to show its usefulness as a neonatal skull phantom.

The study of functional connectivity among different regions of the brain is tremendously valuable in the diagnosis and monitoring of various neurological disorders. While the conventional techniques fail to provide optimum results in terms of resolution, field of view and efficiency, Photo-acoustic based imaging is being considered as an alternative and complimentary modality. The cost and size are the factors that limit the further research and clinical advancements of fcPAT. Therefore we proposed an inexpensive fcPAT system. We determined its feasibility by imaging a graphite leads embedded in an agar phantom and demonstrated its application by imaging a microtubes filled with blood embedded in the chicken’s breast at a scan time of 50 seconds and number of angles as 300.

The increasing use of mouse models for human brain disease studies, coupled with the fact that existing high-resolution functional imaging modalities cannot be easily applied to mice, presents an emerging need for a new functional imaging modality. Utilizing both mechanical and optical scanning in the photoacoustic microscopy, we can image spontaneous cerebral hemodynamic fluctuations and their associated functional connections in the mouse brain. The images is going to be acquired noninvasively with a fast frame rate, a large field of view, and a high spatial resolution. We developed an optical resolution photoacoustic microscopy (OR-PAM) with diode laser. Laser light was raster scanned due to XY-stage movement. Images from ultra-high OR-PAM can then be used to study brain disorders such as stroke, Alzheimer’s, schizophrenia, multiple sclerosis, autism, and epilepsy.

Advances in genetic mapping and sequencing techniques have led to substantial progress in the study of rare monogenic (Mendelian) forms of abnormal blood pressure. Many disease-defining pathways for hypertension have been identified in the past two decades. Perturbations in renal salt handling appear to be a common mechanism underlying these rare syndromes of hypertension. Excess activation at various points in the mineralocorticoid signaling pathway and malfunctioning of the autonomic (specifically sympathetic) nervous system have both been implicated in inducing hypertension, while complementary studies examining low blood pressure phenotypes have identified novel pathways exclusively linked to renal salt wasting in either the thick ascending limb or the distal nephron. The genetic defects and the physiological and cellular pathways affected in these various disorders are reviewed here. Importantly, studies have suggested that genetic variation affecting these same genes and pathways may play an important role in explaining the variation of blood pressure levels in the general population. The investigation of rare syndromes of human blood pressure variation has important implications for improving the diagnosis and treatment of hypertension.

Few studies have investigated the association between hyperuricemia and subclinical myocardial dysfunction. The authors analyzed the relationship between serum uric acid and subclinical markers of heart failure in participants in the Framingham Offspring Cohort (N=2169, mean age 57.3 years, 55.4% women). Cardiac dysfunction was assessed through echocardiographic measurements of left ventricular (LV) mass and thickness, end-diastolic LV thickness, and LV fractional shortening at the sixth visit, approximately 24 years after study onset. Participants in the highest serum uric acid quartile (≥ 6.2 mg/dL serum uric acid) had a significantly greater frequency of echocardiographic abnormalities compared with those in the lowest quartile (

Allopurinol is used to lower serum uric acid (sUA) levels in gout patients. The objective of this study was to investigate the influence of physician specialty on allopurinol treatment patterns and sUA control.This was a retrospective study using claims from a managed care database of US health plan enrollees. Gout patients at least 18 years of age who received allopurinol were identified from the database between January 1, 2002 and April 30, 2007. The index date was defined as the date of the earliest allopurinol claim, and patients were required to have health plan enrollment for at least 365 days prior to and following the index date for inclusion. Physician specialty was determined using the index allopurinol claim. Dosage of allopurinol prescription(s) and number of gout flares were determined from claims data. sUA measurements were used to assess goal attainment over a period of at least one year following the index allopurinol prescription.There were 3363 patients with gout of whom 69.9% received an index allopurinol prescription from a generalist/internist, 5.7% from a rheumatologist, 2.6% from a nephrologist, and 21.8% from a physician with other specialty. Of patients receiving their index prescription from a nephrologist, 38.7% reached the sUA goal of6 mg/dL (357 μmol/L), as compared to patients prescribed by a rheumatologist, generalist/internist, or other physician (35.4%, 31.4%, and 39.4%, respectively; P = 0.015). When controlling for patient characteristics, multivariate analysis did not reveal statistically significant different odds of sUA goal attainment based on prescribing physician specialty, though separate analyses indicated that patients prescribed by a nephrologist had fewer gout flares. Change in allopurinol dosage from initial to final dose was more frequent among patients prescribed by rheumatologists and nephrologists.There is significant heterogeneity in the specialists' management of sUA levels in patients with gout, possibly reflecting differences in case mix and treatment approaches. Limitations related to the use of claims data, such as inability to observe medications filled over-the-counter, should be considered when interpreting study results.

Summary Congenital anomalies of the kidney and urinary tract anatomy (CAKUT) are common in children and represent approximately 30% of all prenatally diagnosed malformations. CAKUT is phenotypically variable and can affect the kidney(s) alone and/or the lower urinary tract. The spectrum includes more common anomalies such as vesicoureteral reflux and, rarely, more severe malformations such as bilateral renal agenesis. In young children, congenital anomalies are the leading cause of kidney failure and for kidney transplantation or dialysis. CAKUT can also lead to significant renal problems in adulthood and may present itself with hypertension and/or proteinuria. Congenital renal anomalies can be sporadic or familial, syndromic (also affecting nonrenal or non–urinary tract tissues), or nonsyndromic. Genetic causes have been identified for the syndromic forms and have shed some light into the molecular mechanisms of kidney development in human beings. The genetic causes for the more common nonsyndromic forms of CAKUT are unknown. The role of prenatal interventions and postnatal therapies as well as the benefits of screening affected individuals and their family members are not clear.

Resting-state functional connectivity (RSFC) is an emerging neuroimaging approach that aims to identify low-frequency, spontaneous cerebral hemodynamic fluctuations and their associated functional connections [1, 2]. Recent research suggests that these fluctuations are highly correlated with local neuronal activity [3, 4]. The spontaneous fluctuations relate to activity that is intrinsically generated by the brain, instead of activity attributable to specific tasks or stimuli [2]. A hallmark of functional organization in the cortex is the striking bilateral symmetry of corresponding functional regions in the left and right hemispheres [5]. This symmetry also exists in spontaneous resting-state hemodynamics, where strong correlations are found inter-hemispherically between bilaterally homologous regions, as well as intra-hemispherically within the same functional regions [3]. Clinical studies have demonstrated that RSFC is altered in brain disorders such as Alzheimer’s [6-12]. Alzheimer’s disease disrupts healthy functional network patterns. Due to its task-free nature, RSFC imaging can be performed on patients under anesthesia [13, 14], on patients unable to perform cognitive tasks [15, 16], and even on patients with brain injury [17, 18]. RSFC imaging is also an appealing technique for studying brain diseases in animal models, in particular the mouse, a species that holds the largest variety of neurological disease models [3, 14, 19, 20]. Compared to clinical studies, imaging genetically modified mice allows exploration of molecular pathways underlying the pathogenesis of neurological disorders [21]. The connection between RSFC maps and neurological disorders permits testing and validation of new therapeutic approaches. However, conventional neuroimaging modalities cannot easily be applied to mice. For instance, in functional connectivity magnetic resonance imaging (fcMRI) [22], the resting-state brain activity is determined via the blood oxygen level dependent (BOLD) signal contrast [23]. The correlation analysis central to RSFC requires a high signal-to-noise ratio (SNR). However, achieving a sufficient SNR is made challenging by the high magnetic fields and small voxel size needed for imaging the mouse brain, as well as the complexity of compensating for field inhomogeneities caused by tissue/bone or tissue/air boundaries [24]. Functional connectivity mapping with optical intrinsic signal imaging (fcOIS) was recently introduced as an alternative method to image RSFC in mice [3, 20]. In fcOIS, changes in hemoglobin concentrations are determined based on changes in the reflected light intensity from the surface of the brain [3, 25]. Therefore, neuronal activity can be measured through the neurovascular response, similar to the method used in fcMRI. However, due to the diffusion of light in tissue, the spatial resolution of fcOIS is limited, and experiments are performed using an exposed skull preparation, which increases the complexity for longitudinal imaging. Here, we utilize optical excitation and acoustic detection, using photoacoustic technology, to noninvasively image RSFC in the mouse brain, with a high frame rate, large field of view and high spatial resolution at different depths. More importantly this will generate a good stand for development of the human functional connectivity photoacoustic tomography system. We call our technique, functional connectivity photoacoustic tomography (fcPAT). Previously we developed an fcPAT with ND:YAG Quanta Ray laser (Pro 270) and a 512-element ring transducer [26]. The system although was fast and accurate, it was costly and could not easily be afforded by neuroscientists to study the RSFC. In the new design of the fcPAT, we use high performance cylindrically focused single element transducers instead of full ring transducer array. The signals obtained from the transducers are amplified with low noise amplifiers. The cylindrical structure where the transducers are placed on, is rotated smoothly to collect photoacoustic signal at different views while the frame rate of the reconstructed image is below one second. We use a solid state laser that has been taken out from a low cost tattoo removal laser machine. FPGA-based National Instrument system is used for data acquisition and processing. Seed-based method is used for extracting RSFC correlation maps. Data acquisition, the reconstruction algorithm and data analysis algorithm are implemented in Labview. The schematic of the setup is shown in Fig.1. An Agar phantom in which eight pencil leads are embedded is imaged, the image of which is shown in Fig.2. The animal protocol was approved last week. We are generating the mouse brain vasculature and functional images from which we obtain RSFC results. The results will be presented in WMIC 2016. Resting-state functional connectivity (RSFC) is an emerging neuroimaging approach that aims to identify low-frequency, spontaneous cerebral hemodynamic fluctuations and their associated functional connections [1, 2]. Recent research suggests that these fluctuations are highly correlated with local neuronal activity [3, 4]. The spontaneous fluctuations relate to activity that is intrinsically generated by the brain, instead of activity attributable to specific tasks or stimuli [2]. A hallmark of functional organization in the cortex is the striking bilateral symmetry of corresponding functional regions in the left and right hemispheres [5]. This symmetry also exists in spontaneous resting-state hemodynamics, where strong correlations are found inter-hemispherically between bilaterally homologous regions, as well as intra-hemispherically within the same functional regions [3]. Clinical studies have demonstrated that RSFC is altered in brain disorders such as Alzheimer’s [6-12]. Alzheimer’s disease disrupts healthy functional network patterns. Due to its task-free nature, RSFC imaging can be performed on patients under anesthesia [13, 14], on patients unable to perform cognitive tasks [15, 16], and even on patients with brain injury [17, 18]. RSFC imaging is also an appealing technique for studying brain diseases in animal models, in particular the mouse, a species that holds the largest variety of neurological disease models [3, 14, 19, 20]. Compared to clinical studies, imaging genetically modified mice allows exploration of molecular pathways underlying the pathogenesis of neurological disorders [21]. The connection between RSFC maps and neurological disorders permits testing and validation of new therapeutic approaches. However, conventional neuroimaging modalities cannot easily be applied to mice. For instance, in functional connectivity magnetic resonance imaging (fcMRI) [22], the resting-state brain activity is determined via the blood oxygen level dependent (BOLD) signal contrast [23]. The correlation analysis central to RSFC requires a high signal-to-noise ratio (SNR). However, achieving a sufficient SNR is made challenging by the high magnetic fields and small voxel size needed for imaging the mouse brain, as well as the complexity of compensating for field inhomogeneities caused by tissue/bone or tissue/air boundaries [24]. Functional connectivity mapping with optical intrinsic signal imaging (fcOIS) was recently introduced as an alternative method to image RSFC in mice [3, 20]. In fcOIS, changes in hemoglobin concentrations are determined based on changes in the reflected light intensity from the surface of the brain [3, 25]. Therefore, neuronal activity can be measured through the neurovascular response, similar to the method used in fcMRI. However, due to the diffusion of light in tissue, the spatial resolution of fcOIS is limited, and experiments are performed using an exposed skull preparation, which increases the complexity for longitudinal imaging. Here, we utilize optical excitation and acoustic detection, using photoacoustic technology, to noninvasively image RSFC in the mouse brain, with a high frame rate, large field of view and high spatial resolution at different depths. More importantly this will generate a good stand for development of the human functional connectivity photoacoustic tomography system. We call our technique, functional connectivity photoacoustic tomography (fcPAT). Previously we developed an fcPAT with ND:YAG Quanta Ray laser (Pro 270) and a 512-element ring transducer [26]. The system although was fast and accurate, it was costly and could not easily be afforded by neuroscientists to study the RSFC. In the new design of the fcPAT, we use high performance cylindrically focused single element transducers instead of full ring transducer array. The signals obtained from the transducers are amplified with low noise amplifiers. The cylindrical structure where the transducers are placed on, is rotated smoothly to collect photoacoustic signal at different views while the frame rate of the reconstructed image is below one second. We use a solid state laser that has been taken out from a low cost tattoo removal laser machine. FPGA-based National Instrument system is used for data acquisition and processing. Seed-based method is used for extracting RSFC correlation maps. Data acquisition, the reconstruction algorithm and data analysis algorithm are implemented in Labview. The schematic of the setup is shown in Fig.1. An Agar phantom in which eight pencil leads are embedded is imaged, the image of which is shown in Fig.2. The animal protocol was approved last week. We are generating the mouse brain vasculature and functional images from which we obtain RSFC results. The results will be presented in WMIC 2016.

Background Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation tool suited to alter cortical excitability and activity via the application of weak direct electrical currents. An increasing number of studies in the addiction literature suggests that tDCS modulates subjective self‐reported craving through stimulation of dorsolateral prefrontal cortex (DLPFC). The major goal of this study was to explore effects of bilateral DLPFC stimulation on resting state networks (RSNs) in association with drug craving modulation. We targeted three large‐scale RSNs; the default mode network (DMN), the executive control network (ECN), and the salience network (SN). Methods Fifteen males were recruited after signing written informed consent. We conducted a double‐blinded sham‐controlled crossover study. Twenty‐minute “real” and “sham” tDCS (2 mA) were applied over the DLPFC on two separate days in random order. Each subject received both stimulation conditions with a 1‐week washout period. The anode and cathode electrodes were located over the right and left DLPFC, respectively. Resting state fMRI was acquired before and after real and sham stimulation. Subjective craving was assessed before and after each fMRI scan. The RSNs were identified using seed‐based analysis and were compared using a generalized linear model. Results Subjective craving decreased significantly after real tDCS compared to sham stimulation (p = .03). Moreover, the analysis shows significant modulation of DMN, ECN, and SN after real tDCS compared to sham stimulation. Additionally, alteration of subjective craving score was correlated with modified activation of the three networks. Discussion Given the observed alteration of the targeted functional brain networks in methamphetamine users, new potentials are highlighted for tDCS as a network intervention strategy and rsfMRI as a suitable monitoring method for these interventions.

The objective of this study was to assess the utility of hyperuricemia as a marker for diabetes and prediabetes (impaired fasting glucose) and insulin resistance in young adults. Using Cox proportional hazards regression models, the authors analyzed 15-year follow-up data on 5,012 persons in 4 US cities who were aged 18-30 years and diabetes-free at the time of enrollment. At baseline (1986), 88% of participants had a body mass index (weight (kg)/height (m)(2)) less than 30. During the follow-up period (through 2001), the incidence rates of diabetes and prediabetes (insulin resistance and impaired fasting glucose) were higher among persons with greater serum urate concentrations. In multivariable Cox regression analyses that adjusted for age, gender, race, body mass index, family history of diabetes, diastolic blood pressure, total cholesterol, smoking, and alcohol use, the hazard ratios for diabetes, insulin resistance, and prediabetes among persons with hyperuricemia (serum urate level >7 mg/dL vs. ≤7.0 mg/dL) were 1.87 (95% confidence interval (CI): 1.33, 2.62), 1.36 (95% CI: 1.23, 1.51), and 1.25 (95% CI: 1.04, 1.52), respectively. This observation was generally consistent across subgroups. The authors conclude that hyperuricemia in the midtwenties is an independent marker for predicting diabetes and prediabetes among young adults in the subsequent 15 years.

There have been substantial recent advances in the pathophysiology of calcium, phosphate, and magnesium disorders. These include the identification of novel transport pathways for magnesium, characterization of the many genetic causes of hypomagnesemia, and the discovery of FGF23, a potent phosphaturic hormone with pleiotropic effects on calcium and phosphate homeostasis. These advances are incorporated in a comprehensive review of the pathophysiology, clinical presentation, and management of these important disorders.

BACKGROUND Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown. METHODS In 95 healthy Asian Indian men, a group known to have a high prevalence of nonalcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non-Asian Indian men. RESULTS Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P

Publisher Summary This chapter provides significant information on mitochondrial diseases of the kidney. Many chronic renal progressive diseases result from nephron degeneration. Focal segmental glomerosclerosis could represent the final common pathway for this degenerative disorder. The initial changes are believed to occur in glomerular epithelial cells. The A3243G point mutation in the tRNALeu is considered to be the most common mtDNA defect. The A3243G mutation is shown to cause type II diabetes with deafness, cardiomyopathy, or progressive external ophthalmoplegia. Oncocytomas are benign tumors predominantly occurring in the kidney. Histologically, they reveal epithelial cells with granular eosinophilic cytoplasm. These cells have an increased number of mitochondria and the mitochondria are dysmorphic. While patients with Fanconi’s syndrome show many electrolyte abnormalities such as hypophosphatemia, hypokalemia, and hypomagnesemia, there are a large number of patients with electrolyte abnormalities and mitochondrial mutations who lack aminoaciduria, acidosis, and glucosuria. There is no effective treatment for diseases of the mitochondria. Treatment is primarily symptomatic. In addition, patients should avoid respiratory chain toxic medications. Patients with complex III deficiency may benefit from vitamin K-3 or coenzyme Q10. Patients with complex I deficiency may be treated with riboflavin. Vitamin C has been prescribed to prevent reactive oxidative species (ROS) damage. Dichloroacetate, an activator of pyruvate dehydrogenase complex, accelerates the oxidation of glucose, lactate, and pyruvate to acetylcoenzyme A. This product has been used at 25-200 mg/kg and improvement has been observed in patients with lactic acidosis.

Familial hypomagnesemic hypercalciuria and nephrocalcinosis (FHHNC [MIM 248250]) is a rare renal tubular disorder characterized by impaired reabsorption of magnesium and calcium in the thick ascending limb of Henle’s loop (tALH), causing renal magnesium wasting and hypercalciuria. Patients with FHHNC usually present with recurrent urinary tract infections, polyuria, nephrolithiasis (NL) and nephrocalcinosis (NC) with many progressing to chronic renal failure (CRF). We have shown recently that loss of function mutations in paracellin-1 PCLN-1/claudin-16, a renal tight junction protein located in the TAL, are causative of FHHNC. We present clinical and molecular studies on a highly inbred family with FHHNC in association with an unusual phenotype in that all affected members were extremely short. Affected individuals were found to be homozygous for marker D3S1314 on chromosome 3q. Sequencing of the PCLN-1/claudin-16 gene revealed a previously unknown point mutation at S235Y on exon 4 on the 4th transmembrane domain, providing additional evidence that inactivating mutations in the PCLN-1/claudin-16 gene result in FHHNC.

Hypertension and dyslipidemia are risk factors for atherosclerosis and occur together more often than expected by chance. Although this clustering suggests shared causation, unifying factors remain unknown. We describe a large kindred with a syndrome including hypertension, hypercholesterolemia, and hypomagnesemia. Each phenotype is transmitted on the maternal lineage with a pattern indicating mitochondrial inheritance. Analysis of the mitochondrial genome of the maternal lineage identified a homoplasmic mutation substituting cytidine for uridine immediately 5′ to the mitochondrial transfer RNA Ile anticodon. Uridine at this position is nearly invariate among transfer RNAs because of its role in stabilizing the anticodon loop. Given the known loss of mitochondrial function with aging, these findings may have implications for the common clustering of these metabolic disorders.

Recent post hoc analyses of large randomized clinical trials have suggested an association between high ESA dose and cardiovascular events (Szczech et al. 2008 KI 74:791). In 2011, implementation of CMS ESRD bundled payment and FDA-mandated ESA label changes that target lower hemoglobin (Hb) created further downward pressure on ESA doses. Long-term safety of intravenous (IV) iron is poorly understood. This study evaluated temporal changes in the ratio of IV iron-to-epoetin use across patients (N=200,170) from a large dialysis organization from 2008 through 2011. Mean IV iron use was normalized to mg/month. Mean epoetin was normalized to U/month. The IV iron-to-epoetin ratio was calculated by taking the mean IV iron value relative to mean epoetin (per 1000U/month) for Q1 2008 – Q4 2011. Although mean epoetin utilization has fallen since start of Q3 2010, mean IV iron utilization has remained fairly stable. From Q1 2008 to Q3 2010, the ratio of IV iron-to-epoetin was constant (2.5 mg/month for every 1000 U per month), but has risen 46% from Q3 2010 to Q4 2011, while hemoglobin levels have fallen 0.9 g/dL (11.5 to 10.6 g/dL). While ESA doses decreased, iron doses remained constant, resulting in a shift toward a higher ratio of iron-to-ESA use from Q3 2010 through Q4 2011. Further analyses are warranted to understand the appropriate balance between iron and ESA use with regards to efficacy and safety Download : Download full-size image

On average ESRD patients are hospitalized twice yearly for 12 days a year (USRDS 2011 Ann. Report). Hb levels decline immediately post-hospitalization, requiring extended periods for recovery and elevated ESA dosing for >1 year (Solid et al. Hemodial Int. 2007). We evaluated post-hospitalization anemia trends and ESA use in ESRD. Data from an LDO (N=273,877 pts; Q1 2008–Q1 2011) were evaluated for post-hosp Hb change (difference, pre- and post-hosp Hb measurement), time to Hb recovery (time from discharge to when Hb levels ≥ pre-hosp level), time to ESA recovery (time from discharge until 3 consecutive non-zero epoetin doses ≤ pre-hosp dose) and incremental ESA (sum of all differences from last pre-hosp dose until ESA recovery, 6 months if no recovery, or end of follow-up for long-term follow-up population). 62% of all hospitalizations were associated with declining Hb (mean, -1.29 g/dL; Figure); 54% of these never returned to pre-hosp levels. Among hospitalizations that experienced a Hb drop and eventually recovered Hb (mean recovery time, 42 days), 73% used a mean 56K U of incremental epoetin until recovery; dose was recovered within 68 days on average. For the remaining 27% who never returned to pre-hosp ESA dose, an additional 266K U of epoetin were utilized. The majority of hospitalizations (∼2/3) had considerable post-hosp Hb drops (mean >1 g/dL), with >50% permanently reduced. ∼1.5 months were needed to recover Hb, with elevated ESA doses for >2 months. ESA dose was permanently elevated in 27% of hospitalizations that recovered Hb. Strategies to address post-hosp anemia may mitigate the protracted recovery time and increased ESA use. Download : Download full-size image

Introduction Patients with a history of myocardial infarction (MI) are often at risk for complications, including subsequent MI and death. Use of prognostic markers may aid in preventing these poor outcomes. Hyperuricemia is associated with increased risk for coronary heart disease (CHD) and/or mortality; however, it is unknown if serum urate (sUA) levels predict outcomes in patients with previous MI. The purpose of this study was to assess hyperuricemia as a biomarker of CHD outcomes in such patients. Methods These were post hoc analyses of datasets from the Aspirin Myocardial Infarction Study, a 1:1 randomized, double-blind clinical trial, conducted from 1975 to 1979, that examined mortality rates following daily aspirin administration over three years in individuals with documented MI. The primary outcome measures were all-cause death, CHD mortality, coronary incidence, and stroke by quartile of baseline sUA. A sub-analysis of all outcome measures in the presence or absence of gouty arthritis was also performed. Results Of 4,524 enrolled participants, data on 4,352 were analyzed here. All outcomes were greatest for patients in the fourth sUA quartile. In multivariate regression models, the hazard ratios (HR) for patients in the highest quartile were 1.88 for all-cause mortality (95% confidence interval (CI), 1.45 to 2.46), 1.99 for CHD mortality (95% CI, 1.49 to 2.66), and 1.36 for coronary incidence (95% CI, 1.08 to 1.70). Participants with untreated gout had an adjusted hazard ratio ranging from 1.5 to 2.0 (all P < 0.01) for these outcomes. Participants with gout who were receiving treatment did not exhibit this additional risk. Conclusions sUA and untreated gout may be independent prognostic markers for poor all-cause and CHD mortality in patients with recent acute MI.

Peginesatide (P) is a synthetic, pegylated, peptide-based ESA approved for treatment of anemia due to chronic kidney disease in adult patients (pts) on dialysis. P demonstrated noninferiority to epoetin (E) in maintenance of Hb levels in hemodialysis (HD) pts in two Phase 3 randomized, active-controlled, open-label trials (EMERALD 1,2). A large dialysis organization (LDO) recently reported an ESA dose adjustment rate of 12.1/pt-year (Bond et al, ISPOR 2012). This post hoc analysis evaluated dosing practices for maintaining Hb with P vs E. Pooled data from the two trials compared P (1x monthly; N=1066) with E (1-3x wkly; N=542) in HD pts previously on stable doses of E. Hb was measured during screening, at baseline and wkly (evaluation period, wks 29-36) or every 2 wks (all other periods). Dose adjustments were not to be made more frequently than every 4 wks, unless required for safety purposes. Dose adjustments (defined as change >±20% from last dose) were evaluated during the titration (wks 0-28), evaluation, and long-term follow-up (LT, wks 36-52) periods. Dose postponements were defined as >35d for P; for E, they were >4d, 6d, or 9d for TIW, BIW, and QW, respectively. Across the entire study period, P doses were adjusted ∼3 times less frequently and held ∼8 times less than P (Table). P (per pt-year) E (per pt-year) E/P ratio Total Dose Adjustments 3.5 10.3 2.9 Dose Increases 1.7 5.3 3.0 Dose Decreases 1.8 5.0 2.8 Dost Postponements 0.6 5.0 8.3 Within each treatment arm, dose adjustment and postponement rates (including corresponding E/P ratios) were similar across titration, evaluation, and LT periods. E dose adjustment rate was similar to that of real world practice in an LDO. E doses were adjusted and held more frequently than P despite similar protocol specifications for dose alteration and Hb maintenance.