Optimal Oral Iron Therapy for Iron Deficiency Anemia Among US Veterans.

Importance: Optimal oral iron supplementation strategy is unclear in patients with iron deficiency anemia (IDA) who have either normal kidney function (NKF) or chronic kidney disease (CKD). Objective: To investigate the association of different oral iron supplementation strategies with the change in hemoglobin and iron indices among patients with IDA with either NKF or CKD. Design, Setting, and Participants: This retrospective cohort study was conducted between 2009 and 2019 at nationwide Veterans Health Administration facilities. Eligible participants included veterans with IDA (defined as hemoglobin <12 g/dL and either iron saturation <20% or ferritin <50 ng/mL) who received their first outpatient prescription of oral iron. Patients were further divided into those with NKF (estimated glomerular filtration rate >60 mL/min/1.73 m2) and CKD (estimated glomerular filtration rate ≥15 mL/min/1.73 m2 and <60 mL/min/1.73 m2). Data analysis was conducted from February to October 2023. Exposures: Patients were classified into 3 groups based on their oral iron dosing schedule: daily (once a day), multiple doses per day (MDD; ≥2 times per day), or alternate-day dose (ADD). Main Outcomes and Measures: The primary outcomes were change of hemoglobin, ferritin, total iron binding capacity (TIBC), and iron saturation (ISAT), which were calculated with linear mixed-effects models. Results: A total of 71 677 veterans with IDA (63 202 male [88.2%] and 8475 female [11.8%]; mean [SD] age, 68.47 [13.09] years), including 47 201 with NKF and 24 476 with CKD, were identifed. In patients with NKF in the daily group, hemoglobin increased from baseline (estimated per-30-day difference [SE], 0.27 [0.00] g/dL; P < .001). In comparison with the daily group, hemoglobin increased more in the MDD group (estimated per-30-day difference [SE], 0.08 [0.03] g/dL; P < .001), but no difference was noted in the ADD group (estimated per-30-day difference [SE], -0.01 [0.01] g/dL; P = .38). Ferritin, ISAT, and TIBC results were similar, except TIBC showed less change in the ADD group compared with the daily group. Patients with CKD showed similar trends but smaller magnitudes in changes. Among patients with NKF, the adjusted mean increase in hemoglobin was 1.03 g/dL (95% CI, 1.01-1.06 g/dL) for those in the daily group, 1.38 g/dL (95% CI, 1.36-1.40 g/dL) for those in the MDD group, and 0.93 g/dL (95% CI, 0.84-1.02 g/dL) for those in the ADD group at 90 days. Among patients with CKD, the adjusted mean increase in hemoglobin was 0.71 g/dL (95% CI, 0.68-0.73 g/dL) for those in the daily group, 0.99 g/dL (95% CI, 0.97-1.01 g/dL) for those in the MDD group, and 0.62 g/dL (95% CI, 0.52-0.73 g/dL) for those in the ADD group at 90 days. Conclusions and Relevance: In this retrospective cohort study of veterans with IDA, there was no significant difference in the improvement of hemoglobin and iron indices between daily and ADD groups, but quickest improvement was observed in the MDD group. These findings suggest that the choice of oral iron therapy should depend on the rapidity of response desired and patient preference due to adverse effects.

Geranylgeraniol (GGOH), incorporated into a bone cement pellet promotes osteoclast function and healing in a model of medication-related osteonecrosis of the jaw.

Introduction: There is no cause -based treatment for Medication-Related Osteonecrosis of the Jaw (MRONJ). MRONJ is a morbid condition including exposed, infected bone and mandibular fractures in osteoporotic individuals and metastatic cancers patients treated with nitrogen containing bisphosphonates (NBP). NBPs inhibit farnesyl diphosphate synthase (FDPS) in the mevalonate pathway, depriving osteoclasts and other bone cells of small GTPases necessary for their function and survival. We test the hypothesis that geranylgeraniol (GGOH),a metabolite downstream of FDPS, when incorporated into a bone cement pellet, enhances osteoclast function and promotes local bone healing in in vitro and in a proven animal model of MRONJ. Methods: 3H labelled GGOH (2 mM) was incorporated into a Hydroset bone cement pellet and release from the cement was assessed over time. To assess the effect on bone cell function, the GGOH-loaded cement was placed in a porous filter above cultured osteoclasts treated with bisphosphonate and the effect on osteoclast survival and function were measured. In a pilot study the effect of GGOH on osteotomy microstructure was measured in a rat model of MRONJ using a split mouth design. Results: The release of GGOH from bone cement increased osteoclast survival/metabolic activity, and promoted resorption of the calcified substrate. In vivo released GGOH limited the effects of the bisphosphonate and promoted healing. In an animal pilot study, GGOH from the infused cement carrier stabilizes bone structure and restores the ability of osteoclasts to remodel. Conclusion: These initial findings point to GGOH in a bone cement carrier as a useful therapeutic approach to prevent or mitigate the pathogenesis of MRONJ.

Olfactory Changes After Military Deployment Are Associated With Emotional Distress but Not With Mild Traumatic Brain Injury History.

OBJECTIVE: The aim of the study was to identify the impact of mild traumatic brain injury history and current emotional status on olfactory functioning. DESIGN: This was a cross-sectional study of 49 predominantly male, military veterans, reservists, and active duty service members with Operations Enduring Freedom, Iraqi Freedom, and New Dawn deployments and varying mild traumatic brain injury histories. RESULTS: Those with a positive history of mild traumatic brain injury (n = 32) endorsed significantly higher rates of self-reported olfactory disturbance. However, there were no differences between the mild traumatic brain injury and no mild traumatic brain injury groups for rates of objective odor identification dysfunction (none vs. microsmia or more severe) or overall accuracy of odor identification. In keeping with this, self-reported olfactory disturbance also failed to associate with odor identification dysfunction. In both groups, those self-reporting olfactory disturbance reported significantly greater emotional distress, severity of posttraumatic stress symptoms, and attentional impulsivity. However, self-reported olfactory disturbance was not associated with other behavioral factors frequently attributed to TBI, such as aggression, motor impulsiveness, poor planning, and cognitive flexibility. CONCLUSIONS: These findings indicate mild traumatic brain injury is not a risk factor for postacute microsomia among Operations Enduring Freedom, Iraqi Freedom, and New Dawn military veterans. Higher observed rates of self-reported olfactory disturbance in patients with mild traumatic brain injury may be a function of emotional distress rather than organic brain injury.

Circulating inflammatory cytokines alter transcriptional activity within fibrotic tissue of Dupuytren's disease patients.

Dupuytren's disease is a benign fibroproliferative disorder of the hand that results in disabling digital contractures that impair function and diminish the quality of life. The incidence of this disease has been correlated with chronic inflammatory states, but any direct association between inflammatory cytokines and Dupuytren's disease is not known. We hypothesized that advanced fibroproliferation is associated with increased levels of circulating inflammatory cytokines. Blood and fibrotic cord tissue were collected preoperatively from patients with severe contracture and control patients. Blood plasma concentrations of known inflammatory cytokines were evaluated using a multiplex immunoassay. Proteins from the cord tissue were analyzed by RNA sequencing and immunohistochemistry. Moreover, collagen-rich cords were analyzed using Fourier-transform infrared spectroscopy. The results indicate that patients exhibited significantly elevated circulating inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-2, and IL-12p70, as compared with controls. Similarly, IL-4 and IL-13 were detected significantly more frequently in Dupuytren's disease as compared with control. RNA sequencing revealed 5311 differentially expressed genes and distinct clustering between diseased and control samples. In addition to increased expression of genes associated with fibroproliferation, we also observed upregulation of transcripts activated by inflammatory cytokines, including prolactin inducible protein and keratin intermediate filaments. IL-2, but not TNF-α, was detected in fibrotic cord tissue by immunohistochemistry. Finally, spectroscopic assays revealed a significant reduction of the collagen content and alterations of collagen cross-linking within the Dupuytren's disease tissues. In total, our results illustrate that patients with severe Dupuytren's disease exhibit substantially elevated circulating inflammatory cytokines that may drive fibroproliferation. Clinical Significance: The results from this study establish the basis for a specific cytokine profile that may be useful for diagnostic testing and therapeutic intervention in Dupuytren's disease.

Intravenous fluids for the prevention of contrast-induced nephropathy in patients undergoing coronary angiography and cardiac catheterization.

Introduction: Contrast-induced nephropathy is a known complication that can occur after intravascular administration of iodinated contrast medium. Its consequences can range from a mild worsening of the renal function to renal failure requiring renal replacement therapy. There is no known effective treatment for contrast-induced nephropathy, and thus, efforts have focused on its prevention. Many approaches have been studied, but the most common strategy in use at the present time is prophylactic intravenous isotonic saline.Areas covered: This article reviews the data supporting the current practice of prophylactic periprocedural intravenous isotonic saline for lowering the incidence of contrast-induced nephropathy. We reviewed PubMed to search primarily for the latest clinical trials and meta-analyses pertaining to contrast-induced nephropathy and the use of prophylactic measures, specifically intravenous infusion of isotonic saline.Expert commentary: Currently, there are no universally accepted methods for the prevention of contrast-induced nephropathy. The best evidence for contrast-induced nephropathy prophylaxis is the administration of intravenous isotonic saline. Our review article provides an overview of the current knowledge, latest research, and current practice on contrast-induced nephropathy prophylaxis using intravenous isotonic saline administration.

iSeqQC: a tool for expression-based quality control in RNA sequencing.

BACKGROUND: Quality Control in any high-throughput sequencing technology is a critical step, which if overlooked can compromise an experiment and the resulting conclusions. A number of methods exist to identify biases during sequencing or alignment, yet not many tools exist to interpret biases due to outliers. RESULTS: Hence, we developed iSeqQC, an expression-based QC tool that detects outliers either produced due to variable laboratory conditions or due to dissimilarity within a phenotypic group. iSeqQC implements various statistical approaches including unsupervised clustering, agglomerative hierarchical clustering and correlation coefficients to provide insight into outliers. It can be utilized through command-line (Github: https://github.com/gkumar09/iSeqQC) or web-interface (http://cancerwebpa.jefferson.edu/iSeqQC). A local shiny installation can also be obtained from github (https://github.com/gkumar09/iSeqQC). CONCLUSION: iSeqQC is a fast, light-weight, expression-based QC tool that detects outliers by implementing various statistical approaches.

Impact of renal function recovery utilizing left ventricular assist device support.

BACKGROUND: In heart failure (HF) patients with renal insufficiency (RI), we hypothesize that mechanical circulatory support (MCS) with the left ventricular assist device (LVAD) will promote renal function recovery (RR). We sought to quantify RR with LVAD support over 6 months of follow-up. METHODS: RR data at 30, 90, and 180 days were analyzed for all LVAD patients with RI at the time of surgery. RI was defined as either the use of hemodialysis (HD) or a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 . RESULTS: Between January 2008 and December 2013, 47 of 127 (37%) LVAD recipients had RI at the time of surgery. The mean preoperative GFR was 48 ± 7. We observed RR at each follow-up, with 30-, 90-, and 180-day mean GFRs of 79 ± 33, 71 ± 31, and 63 ± 21, respectively. The absolute increase in GFR at 30, 90, and 180 days was 34 ± 31, 26 ± 29, and 19 ± 20, respectively (All with P < .001). Four patients (8.5%) with RI required HD preoperatively. Of these, three recovered renal function, the fourth patient died. An additional 13 patients (30.2%) that were previously non-HD-dependent required HD postoperatively. Six of these 13 (46%) recovered renal function during the study period, four (30.7%) remain on HD and three (23%) died. CONCLUSIONS: RI improves significantly with LVAD support. Improvements in GFR are marked in the first 30 days. Among those patients requiring either pre- or post-operative HD, a majority recovered renal function.

Novel mutation in Teneurin 3 found to co-segregate in all affecteds in a multi-generation family with developmental dysplasia of the hip.

DDH is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the hip, suboptimal joint function and accelerated wear of the articular cartilage resulting in early onset crippling arthritis of the hip in 20-40 year olds. Current diagnostic tests in newborns using physical manipulation of the femur or ultrasound either under or over-diagnose this condition. Developing an accurate, cost effective diagnostic test is a goal of this study. To better understand the biologic pathways involved in acetabular development, DNA from severely affected individuals in a four generation family that showed inter-generational transmission of the disorder was isolated and whole exome sequenced. A novel A to C transversion at position 183721398 on human chromosome four was found to co-segregate with the affected phenotype in this family. This mutation encodes a glutamine to proline change at position 2665 in the Teneurin 3 (TENM3) gene and was judged damaging by four prediction programs. Eight week old knock-in mutant mice show delayed development of the left acetabulum and the left glenoid fossa as shown by the presence of more Alcian blue staining on the socket rims of both the hip and the shoulder. We hypothesize that mutated TENM3 will slow chondrogenesis. MMP13 has been shown to impair extracellular matrix remodeling and suppress differentiation. Bone marrow cells from the knock-in mouse were found to overexpress MMP13 with or without BMP2 stimulation. This variant may elucidate pathways responsible for normal hip development and become part of an accurate test for DDH. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

A murine model for developmental dysplasia of the hip: ablation of CX3CR1 affects acetabular morphology and gait.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a debilitating condition whose distinguishing signs include incomplete formation of the acetabulum leading to dislocation of the femur, accelerated wear of the articular cartilage and joint laxity resulting in osteoarthritis. It is a complex disorder having environmental and genetic causes. Existing techniques fail to detect milder forms of DDH in newborns leading to hip osteoarthritis in young adults. A sensitive, specific and cost effective test would allow identification of newborns that could be non-invasively corrected by the use of a Pavlik harness. Previously, we identified a 2.5 MB candidate region on human chromosome 3 by using linkage analysis of a 4 generation, 72 member family. Whole exome sequencing of the DNA of 4 severely affected members revealed a single nucleotide polymorphism variant, rs3732378 co-inherited by all 11 affected family members. This variant causes a threonine to methionine amino acid change in the coding sequence of the CX3CR1 chemokine receptor and is predicted to be harmful to the function of the protein To gain further insight into the function of this mutation we examined the effect of CX3CR1 ablation on the architecture of the mouse acetabulum and on the murine gait. METHODS: The hips of 5 and 8 weeks old wild type and CX3CR1 KO mice were analyzed using micro-CT to measure acetabular diameter and ten additional dimensional parameters. Eight week old mice were gait tested using an inclined treadmill with and without load and then underwent micro-CT analysis. RESULTS: (1) KO mice showed larger a 5-17% larger diameter left acetabula than WT mice at both ages. (2) At 8 weeks the normalized area of space (i.e. size discrepancy) between the femur head and acetabulum is significantly larger [38% (p = 0.001)-21% (p = 0.037)] in the KO mice. (3) At 8 weeks gait analysis of these same mice shows several metrics that are consistent with impairment in the KO but not the WT mice. These deficits are often seen in mice and humans who develop hip OA. CONCLUSION: The effect of CX3CR1 deletion on murine acetabular development provides suggestive evidence of a susceptibility inducing role of the CX3CR1 gene on DDH.

Correction of hyponatraemia improves cognition, quality of life, and brain oedema in cirrhosis.

BACKGROUND & AIMS: Hyponatraemia in cirrhosis is associated with impaired cognition and poor health-related quality of life (HRQOL). However, the benefit of hyponatraemia correction is unclear. The aim of this study was to evaluate the effect of tolvaptan on serum sodium (Na), cognition, HRQOL, companion burden, and brain MRI (volumetrics, spectroscopy, and diffusion tensor imaging) in cirrhotics with hyponatraemia. METHODS: Cirrhotics with Na <130 mEq/L were included for a four-week trial. At screening, patients underwent cognitive and HRQOL testing, serum/urine chemistries and companion burden assessment. Patients then underwent fluid restriction and diuretic withdrawal for two weeks after which cognitive tests were repeated. If Na was still <130 mEq/L, brain magnetic resonance imaging (MRI) was performed and tolvaptan was initiated for 14 days with frequent clinical/laboratory monitoring. After 14 days of tolvaptan, all tests were repeated. Comparisons were made between screen, pre-and post-drug periods Na, urine/serum laboratories, cognition, HRQOL and companion burden. RESULTS: 24 cirrhotics were enrolled; seven normalized Na without tolvaptan with improvement in cognition. The remaining 17 received tolvaptan of which 14 completed the study over 13 ± 2 days (age 58 ± 6 years, MELD 17, 55% HCV, median 26 mg/day of tolvaptan). Serum Na and urine free water clearance increased with tolvaptan without changes in mental status or liver function. Cognitive function, HRQOL and companion burden only improved in these 14 patients after tolvaptan, along with reduced total brain and white matter volume, increase in choline on magnetic resonance spectroscopy, and reduced cytotoxic oedema. CONCLUSIONS: Short-term tolvaptan therapy is well tolerated in cirrhosis. Hyponatraemia correction is associated with cognitive, HRQOL, brain MRI and companion burden improvement.

Linkage mapping and whole exome sequencing identify a shared variant in CX3CR1 in a large multi-generation family.

Developmental dysplasia of the hip (DDH) is a crippling condition that affects children and adults, with an average incidence of 1-1.5 cases per 1000 live births. It results in disabling arthritis of the hip in up to 60% patients in the 20-40 year age group. There is no accurate diagnostic test available for newborns. The purpose of our study is to develop a sensitive and specific genetic test for DDH by identifying causative mutations. Linkage analysis and whole exome sequencing of 4 severely affected individuals of a 4 generation 71 member family was performed. The damaging rs3732378 variant in the CX3CR1 chemokine receptor was shared by all affected family members and by 15% of 28 sporadic dysplastics.

Redox and light control the heme-sensing activity of AppA.

UNLABELLED: The DNA binding activity of the photosystem-specific repressor PpsR is known to be repressed by the antirepressor AppA. AppA contains a blue-light-absorbing BLUF domain and a heme-binding SCHIC domain that controls the interaction of AppA with PpsR in response to light and heme availability. In this study, we have solved the structure of the SCHIC domain and identified the histidine residue that is critical for heme binding. We also demonstrate that dark-adapted AppA binds heme better than light-excited AppA does and that heme bound to the SCHIC domain significantly reduces the length of the BLUF photocycle. We further show that heme binding to the SCHIC domain is affected by the redox state of a disulfide bridge located in the Cys-rich carboxyl-terminal region. These results demonstrate that light, redox, and heme are integrated inputs that control AppA's ability to disrupt the DNA binding activity of PpsR. IMPORTANCE: Photosynthetic bacteria must coordinate synthesis of the tetrapyrroles cobalamin, heme, and bacteriochlorophyll, as overproduction of the latter two is toxic to cells. A key regulator controlling tetrapyrrole biosynthesis is PpsR, and the activity of PpsR is controlled by the heme-binding and light-regulated antirepressor AppA. We show that AppA binds heme only under dark conditions and that heme binding significantly affects the length of the AppA photocycle. Since AppA interacts with PpsR only in the dark, bound heme thus stimulates the antirepressor activity of PpsR. This causes the redirection of tetrapyrrole biosynthesis away from heme into the bacteriochlorophyll branch.

Developmental dysplasia of the hip: linkage mapping and whole exome sequencing identify a shared variant in CX3CR1 in all affected members of a large multigeneration family.

Developmental dysplasia of the hip (DDH) is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the femur, suboptimal joint function, and accelerated wear of the articular cartilage resulting in arthritis. DDH affects 1 in 1000 newborns in the United States; there are well-defined "pockets" of high prevalence in Japan, and in Italy and other Mediterranean countries. Although reasonably accurate for detecting gross forms of hip dysplasia, existing techniques fail to find milder forms of dysplasia. Undetected hip dysplasia is the leading cause of osteoarthritis of the hip in young individuals, causing over 40% of cases in this age group. A sensitive and specific test for DDH has remained a desirable yet elusive goal in orthopedics for a long time. A 72-member, four-generation affected family has been recruited, and DNA from its members retrieved. Genomewide linkage analysis revealed a 2.61-Mb candidate region (38.7-41.31 Mb from the p term of chromosome 3) co-inherited by all affected members with a maximum logarithm (base 10) of odds (LOD) score of 3.31. Whole exome sequencing and analysis of this candidate region in four severely affected family members revealed one shared variant, rs3732378, that causes a threonine (polar) to methionine (non-polar) alteration at position 280 in the transmembrane domain of CX3CR1. This mutation is predicted to have a deleterious effect on its encoded protein, which functions as a receptor for the ligand fractalkine. By Sanger sequencing this variant was found to be present in the DNA of all affected individuals and obligate heterozygotes. CX3CR1 mediates cellular adhesive and migratory functions and is known to be expressed in mesenchymal stem cells destined to become chondrocytes. A genetic risk factor that might be among the etiologic factors for the family in this study has been identified, along with other possible aggravating mutations shared by four severely affected family members. These findings might illuminate the molecular pathways affecting chondrocyte maturation and bone formation.

Variable expression and incomplete penetrance of developmental dysplasia of the hip: clinical challenge in a 71-member multigeneration family.

Developmental dysplasia of the hip is a crippling condition that affects children and adults. Identical twin studies support a strong causative genetic component. Although clinical tests for newborns can detect gross malformations, it is the subtle malformations that are often not detected, resulting in early onset osteoarthritis of the hip in adults. As a first step in identifying the causative mutation, we have recruited the largest documented affected family with 71 members spanning generations. Clinical and radiographic signs of developmental dysplasia of the hip are described, and the diagnostic challenge of identifying affected family members is discussed.Variable expression of disease allele is evident in several members of the family and greatly contributes to the diagnostic challenge facing clinicians.

The Otto Aufranc Award: Identification of a 4 Mb region on chromosome 17q21 linked to developmental dysplasia of the hip in one 18-member, multigeneration family.

Developmental dysplasia of the hip (DDH) is a disabling condition that, depending on geography, can afflict between 20% and 80% of patients with end-stage arthritis of the hip. Despite its prevalence, the etiology of this disease remains unknown. DDH is a complex disorder with both environmental and genetic causes. Based on the literature the candidate genes for the disease are HOXB9, collagen type I alpha1, and DLX 3. The purpose of our study was to map and characterize the gene or genes responsible for this disorder by family linkage analysis. We recruited one 18-member, multigeneration affected family to provide cheek swabs and blood samples for isolation of DNA. Amplified DNA underwent a total genome scan using GeneChip Mapping 250 K Assay (Affymetrix, Santa Clara, CA). We observed only one region with a LOD score greater than 1.5: a 4 Mb region on chromosome 17q21.32, yielding a LOD score of 1.82. While a LOD score of 1.82 does not meet the accepted standard for linkage we interpret these data as suggesting the responsible gene could be linked to this region, which includes a cluster of homeobox genes (HOX genes) that are part of the developmental regulatory system providing cells with specific positional identities along the developing joint and spine. Discovering the genetic basis of the disease would be an important step in understanding the etiology of this disabling condition.

Utilization of excimer laser debulking for critical lesions unsuitable for standard renal angioplasty.

BACKGROUND: The energy emitted by ultraviolet laser is avidly absorbed in atherosclerotic plaques. Conceptually, it could be applied for debulking of selected atherosclerotic renal artery stenoses. We describe early experience with revascularization of critical renal artery lesions deemed unsuitable for standard renal angioplasty. Institutional Review Board permission to conduct the data analysis was obtained. METHODS: Among 130 percutaneous renal artery interventions with balloon angioplasty and adjunct stenting, there were 12 (9%) patients who underwent laser debulking prior to stenting. These patients presented with critical (95+/-3.5% stenoses) lesions (11 de novo, 1 stent restenosis) deemed unsuitable for standard renal angioplasty because of marked eccentricity and presence of thrombus. Indications for intervention included preservation of kidney function, treatment of uncontrolled hypertension, management of congestive heart failure, and treatment of unstable angina. Blood pressure and estimated glomerular filtration rate (eGFR) were measured pre- and 3 weeks post-intervention. RESULTS: A baseline angiographic stenosis of 95+/-3.5% was reduced to 50+/-13% with laser debulking. There were no laser-induced complications. Post-stenting the angiographic residual stenosis was 0%. The mean gradient across the lesions was reduced from baseline 85+/-40 to 0 mmHg. A normal post-intervention antegrade renal flow was observed in all patients. Baseline mean systolic BP of 178+/-20 mmHg decreased to 132+/-12 mmHg (P<0.0001) and mean diastolic pressure of 85+/-16 mmHg reduced to 71+/-9 mmHg (P = 0.01). A pre-intervention mean eGFR of 47.7+/-19 ml/min/1.73 m(2) increased to 56+/-20.4 ml/min/1.73 m(2) (P = 0.05) post-procedure. The interventions were not associated with major renal or cardiac adverse events. During follow-up one patient developed transient contrast-induced nephropathy. CONCLUSIONS: Debulking of select renal artery stenoses with laser angioplasty followed by adjunct stenting is feasible. Further prospective, randomized studies will be required to explore the role of debulking and laser angioplasty in renal artery revascularization.

Human salt taste and the lingual surface potential correlate.

We have demonstrated in humans that Na(+) evokes changes in the lingual surface potential (LSP) using a custom chamber. To assess whether a relationship exists between the Na(+)-evoked changes in the LSP and the intensity of salt taste, we measured the LSP and the intensity of salt taste simultaneously in 7 subjects using test solutions (50, 100, 300, and 1000 mM NaCl) presented in random order. The evoked LSPs and intensity scores correlated with one another well (r(2) = 0.992, P < 0.01). We then screened 14 subjects for their ability to discriminate between 100 and 300 mM NaCl using the chamber. Three subjects were consistently capable of distinguishing the salt concentrations. In these 3 subjects, an inhibitor of the epithelial sodium channel, amiloride (10 muM), blocked the ability to distinguish salt concentrations and affected the LSP. These data suggest that the LSP may be a component of the signal transduction system involved in human salt taste. In adept salt tasters, an amiloride-sensitive mechanism appears to have a role in distinguishing salt concentrations.

Estimating dialysis adequacy using ionic dialysance.

The aim of this study was to determine the efficacy and feasibility of estimating dialysis adequacy using ionic dialysance (ID). We retrospectively reviewed the medical records of patients receiving thrice weekly dialysis for an eight-month period at a single-center Veterans Affairs hospital. Dialysis adequacy was determined monthly using pre- and post-treatment BUN measurements to calculate the single pool Kt/V (spKt/V) with the formula set forth by Daugirdas. On the same treatment day, K(ID)t was determined by multiplying the average ID times the time (t) of the treatment. A surrogate volume, V(ID), was estimated by dividing K(ID)t by spKt/V using data from the first six months. During the subsequent two months, we compared dialysis adequacy estimated by urea-based spKt/V to ionic dialysance based K(ID)t/V(ID) utilizing V(ID). In the first month, K(ID)t/V(ID) estimations and the simultaneous spKt/V determinations averaged 1.55 +/- 0.36 and 1.59 +/- 0.42, respectively. In the second month, K(ID)t/V(ID) and spKt/V averaged 1.52 +/- 0.33 and 1.54 +/- 0.35, respectively. K(ID)t/V(ID) correlated well with spKt/V, as the slope was 0.85 (r = 0.95, p < 0.001). There was considerable intra-patient variability of K(ID), time, and K(ID)t/V(ID) with coefficient of variations (CV) of 8.4 +/- 4.3, 9.0 +/- 5.3, and 15.8 +/- 9.2, respectively. However, the CV for K(ID)t/V(ID) was similar to the CV for spKt/V (15.3 +/- 7.4). These results suggest that it is possible to estimate dialysis adequacy during every treatment using K(ID)t/V(ID). Furthermore, there is considerable variability in the delivered dialysis adequacy, suggesting that many sessions result in sub-optimal dialysis.

Over-expression of BMP4 and BMP5 in a child with axial skeletal malformations and heterotopic ossification: a new syndrome.

Bone morphogenetic proteins (BMPs) are a highly conserved class of signaling molecules that induce ectopic cartilage and bone formation in vivo. Dysregulated expression of bone morphogenetic protein 4 (BMP4) is found in the cells of patients who have fibrodysplasia ossificans progressiva (FOP), a genetic disorder of axial and appendicular skeletal malformation and progressive heterotopic ossification. Loss of function mutations in the bone morphogenetic protein 5 (bmp5) gene leading to under-expression of BMP5 cause the murine short ear syndrome, characterized by small malformed ears and a broad range of axial skeletal malformations. We found features reminiscent of both the short ear mouse and FOP in a child with malformed external ears, multiple malformations of the axial skeleton, and progressive heterotopic ossification in the neck and back. We examined BMP mRNA expression in transformed lymphocytes by semi-quantitative RT-PCR and protein expression by ELISA assays and immunohistochemistry. Elevated levels of BMP4 and BMP5 mRNA and protein were detected in the patient's cells while levels of BMP2 mRNA were unchanged. Our data suggest that dysregulated expression of BMP4 and BMP5 genes is associated with an array of human axial skeletal abnormalities similar to the short ear mouse and FOP.