Vaginal peritoneum fistula through pouch of Douglas during peritoneal dialysis: Case report and literature review.

INTRODUCTION: Peritoneal dialysis is the preferred approach for kidney replacement therapy. A peritoneal-vaginal fistula is a rare complication associated with peritoneal dialysis. CASE PRESENTATION: A 69-year-old woman with a history of type two diabetes and systemic arterial hypertension for twenty years is scheduled to undergo the surgical placement of a Tenckoff catheter to begin renal replacement therapy. After having thirty dialysis sessions, she was discharged to continue therapy at home. Five days later, she observed a notable rise in vaginal discharge after peritoneal dialysis. This case report investigates the etiology, diagnosis, and management of peritoneal vaginal fistula and analyzes current medical literature. DISCUSSION: Factors associated with the formation of peritoneum-vaginal fistula include increased intra-abdominal pressure due to dialysis, anatomical predisposition, peritonitis, and malnutrition. CONCLUSIONS: Peritoneal vaginal fistula is an uncommon consequence of peritoneal dialysis. Diagnosis entails demonstrating the movement of dialysis fluid from the peritoneum to the vagina. Treatment should be customized according to the etiology of the fistula and the individual needs of each patient.

Influence of anterior chamber depth and vault on anterior chamber angle morphology after phakic posterior chamber intraocular lens implantation.

PURPOSE: This study aims to investigate the influence of anterior chamber depth (ACD) and vault on the anterior chamber angle (ACA) morphology in myopic individuals implanted with posterior chamber phakic intraocular lenses. METHODS: This retrospective case series involved 231 eyes receiving a 13.2-mm implantable collamer lens (ICL). Preoperative anterior chamber anatomy was assessed using anterior segment optical coherence tomography (AS-OCT) and optical tomography, while postoperative evaluation employed AS-OCT. ACA morphology was characterized pre- and postoperatively through trabecular iris angle (TIA750), ACA distance opening (AOD750) and trabecular iris space area (TISA750). The influence of ACD and vault was examined by categorizing the sample into ACD (shallow, average and deep) and vault (low, optimal and high) groups. RESULTS: Preoperative ACA morphology varied based on ACD, with shallower ACDs exhibiting narrower TIA750, smaller AOD750 and TISA750. ICL implantation induced greater ACA narrowing more in the deep ACD group (TIA750 = 20.1 degrees; AOD750 = 0.82 mm and TISA750 = 0.44 mm2) compared to the shallow ACD group (TIA750 = 15.2 degrees; AOD750 = 0.44 mm and TISA750 = 0.21 mm2). Postoperatively, deeper ACDs showed larger ACAs. Increasing vault magnitude led to increased ACA narrowing, with the low vault group exhibiting smaller closure (TIA750 = 14.3 degrees; AOD750 = 0.56 mm and TISA750 = 0.29 mm2) compared to the high vault group (TIA750 = 20.8 degrees; AOD750 = 0.73 mm and TISA750 = 0.36 mm2). The magnitude of ACA narrowing associated with the vault had a consistent effect across different ACD groups. CONCLUSIONS: Posterior chamber intraocular lens implantation results in ACA narrowing, the extent of which is contingent upon preoperative anterior chamber and ACA morphology, with additional influence from vault magnitude.

Prediction model of the horizontal trabecular iris angle after phakic posterior chamber implantable intraocular lens surgery.

PURPOSE: To determine the predictors of the postoperative horizontal trabecular iris angle (TIA 750 ) after phakic posterior chamber implantable intraocular lens (IOL) surgery. SETTING: Ophthalmology Clinic Vista Sánchez Trancón, Badajoz, Spain. DESIGN: Retrospective case series. METHODS: 330 eyes implanted with spherical/toric implantable collamer lens (ICL) were included in this study. From 230 eyes implanted with 13.2 mm ICL, these were divided in modeling (n = 180) and evaluation group (n = 50). Two groups implanted with 12.6 mm and 13.7 mm (n = 50 each) were also used as evaluation. Anterior-segment optical coherence tomography was used preoperatively to perform anterior chamber biometry (angle-to-angle [ATA] distance, crystalline lens rise, anterior chamber depth [ACD], cornea sagittal depth, pupil diameter, nasal/temporal TIA 750 ); postoperatively for measuring the vault, pupil diameter and nasal/temporal TIA 750 . Corneal curvature and horizontal visible iris diameter were measured using optical tomography. Bivariate correlation analysis was used to determine associations between preoperative and postoperative horizontal TIA 750 with anterior chamber biometry, ICL-related parameters and age. Finally, a multivariate linear regression model was constructed for predicting the postoperative TIA 750 . RESULTS: Horizontal TIA 750 reduced from 42.9 ± 8.0 degrees preoperatively to 24.4 ± 5.6 degrees postoperatively. Postoperative TIA 750 was positively correlated with the preoperative TIA 750 , cornea sagittal depth and ACD, and negatively associated with the vault. The main predictors of the postoperative TIA 750 were the preoperative parameters, TIA 750 , ICLsize - ATA and pupil diameter (adjusted- R2 = 0.39). The limits of agreement between predicted and real TIA 750 were close to ±10 degrees. CONCLUSIONS: Implantation of a phakic posterior chamber implantable IOL leads to a reduction in TIA 750 and the main factors contributing for this are the preoperative TIA 750 aperture and the vault.

Repeatability and agreement of swept-source optical coherence tomography and partial coherence interferometry biometers in myopes.

CLINICAL RELEVANCE: Biometric measurements in the context of myopia are fundamental to detect eyes at risk of developing myopia and during the follow-up of patients with myopia control treatment. Thus, the accuracy of biometers has high clinical relevance. BACKGROUND: The Myopia Master is a new biometer based on partial coherence interferometry especially dedicated to the follow-up of myopic patients. This study aims to assess the repeatability of the Myopia Master and evaluate its agreement with a swept-source optical coherence interferometry biometer (IOL Master 700). METHODS: This cross-sectional prospective study assessed the biometric parameters of two groups of myopes (age range: 8-16 years old), spectacle corrected (n = 60) and orthokeratology contact lens wearers (n = 60). One senior optometrist performed two consecutive measurements per instrument, which included axial length, mean keratometry and horizontal visible iris diameter (HVID). The repeatability of each device and the agreement between devices were assessed by the dispersion of the measurement differences, for AL, mean keratometry, corneal astigmatism and HVID. RESULTS: The two biometers measured approximately the same value in both measurements. Test-retest repeatability tended to be lower than clinical significant thresholds, in particular, for AL and mean keratometry. Corneal-related parameters tended to have lower repeatability in the orthokeratology group, especially mean keratometry. The agreement between instruments revealed statistically significant differences between devices with the SS-OCT measuring longer eyes, steeper corneas and larger HVID. CONCLUSIONS: In a paediatric population, the Myopia Master showed clinically acceptable repeatability levels, but the IOL Master 700 demonstrated superior repeatability. Eyes treated with orthokeratology may compromise the repeatability of the corneal-related parameters. The Myopia Master and the IOL Master 700 are repeatable devices appropriate for monitoring myopia progression, but the differences observed do not allow their use interchangeably.

Vault differences in eyes implanted with spherical and toric implantable collamer lenses: an inter-eye analysis.

PURPOSE: To determine the influence of implantable collamer lenses (ICL) geometry, i.e. spherical and toric on the vault, and report the refractive and visual outcomes of patients bilaterally implanted with the two ICL geometries. METHODS: This retrospective case series analysed 41 patients implanted with a spherical ICL (sICL) in one eye and an equal sized toric ICL (tICL) in the fellow eye. The anatomical and ICL-related parameters were assessed using anterior-segment optical coherence tomography (AS-OCT Visante, Zeiss Meditec AG) and optical tomography (Pentacam, OCULUS). The influence of the anatomical and ICL-related parameters on the vault was determined using generalised estimating equations (GEE) to incorporate inter-eye correlations. RESULTS: Postoperative spherical equivalent was within ± 0.50D in 66% and 83% of the eyes, respectively implanted with sICL and tICL. The efficacy index in the sICL group was 1.06 and 1.14 in the tICL group. The mean inter-eye vault difference was -1.46 µm, anatomical and ICL-related parameters showed similar associations with the vault for sICL and tICL. The GEE identified the ICL size minus the anterior chamber width, the ICL spherical power and ICL central thickness as significant factors influencing the vault. CONCLUSIONS: Spherical and toric ICL showed good efficacy for the correction of myopia and astigmatism. Patients implanted bilaterally with sICL and tICL tend to present similar vaults. The vault produced by both types of ICL was mainly regulated by the oversizing of the ICL. This suggests that the ICL geometry (spherical vs toric) is a factor with limited influence on the vault, thus the sizing method of a sICL and tICL should be similar.

Biometric and ICL-related risk factors associated to sub-optimal vaults in eyes implanted with implantable collamer lenses.

BACKGROUND: To identify biometric and implantable collamer lens (ICL)-related risk factors associated with sub-optimal postoperative vault in eyes implanted with phakic ICL. METHODS: This study reports a retrospective case series of the first operated eye in 360 patients implanted with myopic spherical or toric ICL. Preoperatively, white-to-white (WTW), central keratometry (Kc) and central corneal thickness (CCT) were measured using the Pentacam. Anterior-segment optical coherence tomography (AS-OCT, Visante) was applied preoperatively for measuring the horizontal anterior-chamber angle-to-angle distance (ATA), internal anterior chamber depth (ACD), crystalline lens rise (CLR), anterior-chamber angle (ACA) and postoperatively the vault. Eyes were divided into three vault groups: low (LVG: ≤ 250 µm), optimal (OVG: > 250 and < 1000 µm) and high (HVG: ≥ 1000 µm). Multinomial logistic regression (MLR) was used to find the sub-optimal vault predictors. RESULTS: MLR showed that CLR, ICL size minus the ATA (ICL size-ATA), age, ICL spherical equivalent (ICLSE) and ICL size as contributing factors for sub-optimal vaults (pseudo-R2 = 0.40). Increased CLR (OR: 1.01, CI: 1.00-1.01) and less myopic ICLSE (OR: 1.22, CI: 1.07-1.40) were risk factors for low vaults. Larger ICL size-ATA (OR: 41.29, CI: 10.57-161.22) and the 13.7 mm ICL (OR: 7.08, CI: 3.16-15.89) were risk factors for high vaults, whereas less myopic ICLSE (OR: 0.85, CI: 0.76-0.95) and older age (OR: 0.92, CI: 0.88-0.98) were protective factors. CONCLUSION: High CLR and low ICLSE were the major risk factors in eyes presenting low vaults. In the opposite direction, ICL size-ATA was the major contributor for high vaults. This relationship was more critical in higher myopic ICLSE, younger eyes and when 13.7 mm ICL were used. The findings show that factors influencing the vault have differentiated weight of influence depending on the type of vault (low, optimal or high).

Inter-Eye Vault Differences of Implantable Collamer Lens Measured Using Anterior Segment Optical Coherence Tomography.

PURPOSE: The distance between an implantable collamer lens (ICL) and the crystalline lens, namely vault, is a space regulated by the interaction of the ICL and the anatomical structures of the eye. This study analysed the differences in vault size between fellow eyes with similar anterior segment biometry. PATIENTS AND METHODS: A retrospective case series analysed 109 cases of patients bilaterally implanted with EVO-V4c. Patients were analysed pre- and postoperatively using anterior segment optical coherence tomography. The range of vault inter-eye differences was defined as the 95% confidence interval of the differences. Bivariate correlation was applied to seek for associations between vault inter-eye differences with biometric and lens parameters (angle-to-angle, anterior chamber depth, crystalline lens rise, central corneal thickness, central keratometry, ICL spherical equivalent, horizontal compression, postoperative pupil diameter and vault). RESULTS: Mean vault inter-eye differences were similar between fellow eyes (26.0 ± 122.5 µm). The 95% confidence interval range of the differences was ±240.1 µm, nearly 50% of the cases presented vault inter-eye differences higher than 100 µm. The vault of the first operated eye explained 81% of the variance in the second eye vault. Vault inter-eye differences were positively correlated with the level of horizontal compression and with vault magnitude. CONCLUSION: Vaults measured in fellow eyes may present considerable differences, which can reach 25% of the common vault range. This reflects some degree of baseline variability in the vault. Clinically, these differences assume special relevance in cases where low or high vaults are expected.

Comparison of two different doses of bleomycin in electrochemotherapy protocols for feline cutaneous squamous cell carcinoma nonsegregated from ultraviolet light exposure.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin tumors in cats due to chronic exposure to ultraviolet light. Local treatments such as electrochemotherapy (ECT) promote disease control or even complete remission. We hypothesize that cats could benefit from treatments using bleomycin at reduced dosages. A prospective nonrandomized single-blind study evaluated the clinical parameters, site lesion, staging, disease-free interval (DFI) and survival time by comparing the standard dose of bleomycin (15,000 UI/m2) (n = 22) with a reduced dose (10,000 UI/m2) (n = 34) in cats with cSCC that underwent ECT as the sole treatment modality. No statistically significant difference in DFI or overall survival was observed between the 2 groups. A higher DFI was found in cats with a small tumor size (less than 0.33 cm3) compared with that for cats with a large tumor size (P = 0.045). Furthermore, a reduced overall survival time for cats with a higher stage in the standard group SG (T3 and T4) (P = 0.004) was observed when compared to that for cats with a lower stage (T1 and T2). In conclusion, ECT using both doses of bleomycin may achieve the same response rate in terms of the overall response, DFI, and overall survival.

Response dataset from canine extramedullary plasmacytoma treated with lipophobic drugs enhanced by electroporation.

Over the past 15 years, lipophobic drugs, such as bleomycin and cisplatin, have been used combined with electroporation, which promotes their uptake through the cell membrane. The present data describe general findings following electrochemotherapy and how plasmacytomas can respond to this technique. We will explain and illustrate specific outcomes during the remission process. The data presented here can be useful for researchers, veterinarians, and pet owners. Furthermore, the data could be useful for other cutaneous or oral tumors in which electrochemotherapy may be indicated. Interpretation of the data and outcomes may be found in the research article entitled "Outcome following curative-intent electrochemotherapy for extramedullary plasmocytoma in dogs - case reports ."

Outcome Following Curative-Intent Electrochemotherapy for Extramedullary Plasmocytoma in Dogs - Case Reports.

Plasma cell tumors can occur as solitary collections referred as extramedullary plasmocytoma (EMP). The present report describes four cases of EMP treated with a local nonthermal ablative approach. Four dogs were diagnosed with extramedullary plasmocytomas (EMP) in different body regions (oral cavity, digits, and lip). Since surgical excision was declined by the owners (maxillectomy; amputation or lip reconstruction), a curative-intent approach was indicated as solely treatment- electrochemotherapy (ECT). All the patients received ECT under general anesthesia using bleomycin intravenously (15,000 UI/m²) or cisplatin intratumorally (1mg/cm³). All dogs developed transitory ulceration and swelling one-week after procedure that completely healed within 30 days post-ECT. Complete remission was achieved in all cases and lasted for 515 (oral case), 695 (one digit), 90 (another digit case) and 240 (lip) days. These results suggested that ECT promoted remission in EMP cases being a possibility for local control in dogs affected by this disease.

Determining vault size in implantable collamer lenses: preoperative anatomy and lens parameters.

PURPOSE: To determine patient preoperative anatomical features and the parameters of implantable collamer lenses (ICLs) relevant in explaining vault variability. SETTING: Ophthalmology Clinic Vista Sánchez Trancón, Badajoz, Spain. DESIGN: Retrospective case series. METHODS: This study comprised 360 eyes of 360 patients implanted with myopic or toric ICLs. Pentacam imaging was used for assessing white-to-white (WTW) diameter, central keratometry, and central corneal thickness. Anterior-segment optical coherence tomography was used to measure the horizontal anterior chamber angle distance (ATA), internal anterior chamber (ACQ), crystalline lens rise (CLR), anterior chamber angle (ACA), and vault. The sample was divided according to the implanted lens size (12.6 mm, 13.2 mm, and 13.7 mm). Vault predictors were identified from the variables above using multivariate regression analysis. RESULTS: The groups showed significant statistical differences for WTW, ATA, ACQ, ACA, and vault (P < .007 for all). In general, bigger lenses were implanted in eyes with larger transverse sizes (WTW and ATA) and deeper ACQ. Also, larger ICL diameters were associated with higher vaults. Multivariate regression analysis identified the lens size (13.2 mm as reference; 12.6 mm: ß [standardized coefficients] = -0.33; 13.7 mm: ß = 0.42), ATA (ß = -0.42), and CLR (ß = -0.25), ICL spherical equivalent (ß = -0.22) and patient age (ß = -0.12) as predictors of the vault size (adjusted-R = 0.34 P < .001). CONCLUSIONS: The multivariate model explained 34% of vault variability. The predictors indicated the presence of different mechanisms regulating the vault. These involved the difference between the transverse size of the eye and the ICL, the crystalline lens protrusion, and the ICL properties, such as power and size.

Hydroxyurea-induced onychomadesis in a dog with chronic myeloid leukemia: A case report.

A 12-year-old Rottweiler dog was presented with a history of prostration, weight loss and hyporexia for six months. Based on complete blood tests (hematological and biochemical analyses), bone marrow examination and imaging analysis, a diagnosis of chronic myeloid leukemia was made. Treatment with hydroxyurea at a dosage of 18 mg/kg twice daily was not effective in controlling the high count of white blood cells. Furthermore, after 35 days of hydroxyurea treatment, the animal developed onycholysis, with sloughing of the claws of the left pelvic and left thoracic limbs and exposure of the distal phalanx. Interruption of the medication was implemented, with clinical healing of the ungual lesions observed three months after initiation of the drug. White blood cells returned to normal after using cyclophosphamide. Currently, the animal is in complete remission, having a disease-free interval of 575 days without chemotherapy. To the authors' knowledge, this is the first report of hydroxyurea-induced onycholysis within a short-term period in a dog diagnosed with chronic myeloid leukemia.

¿Es posible la detección temprana por ecografía del hemotórax coagulado postraumático? / Is the early detection of post-traumatic retained clotted hemothorax possible?

El propósito de este estudio fue determinar la presencia de la coagulación del hemotórax como un fenómeno temprano y visible por ecografía, en los pacientes con derrame posterior al trauma de tórax. Se evaluaron, de manera descriptiva y prospectiva, las características clínicas y ecográficas de los pacientes que presentaron hemotórax o hemoneumotórax traumático, entre enero de 2011 y marzo de 2014. Se practicó ecografía de tórax a 68 pacientes que presentaron este tipo de lesiones y se encontró la presencia temprana de coágulos en 9 de ellos, de los cuales solo uno presento hemotórax retenido como complicación. El 1/9 de los pacientes con coágulos desarrollan hemotórax coagulado, en tanto que 4/59 de aquellos sin coágulos lo desarrollan (riesgo relativo, RR=1,65; IC95% 0,20-1,31). Se concluyó que no había relación entre la aparición temprana de coágulos y el desarrollo de hemotórax. Se requieren estudios con un mayor número de pacientes para demostrar esta asociación

The objective of this study was to determine the presence of retained clotted hemothorax as an early phenomenon visible by ultrasound in patients with pleural effusion posterior to thoracic trauma. We prospectively and descriptively assessed the clinical and ultrasound characteristics of patients who presented traumatic hemothorax or hemopneumothorax in the period January 2011 to March 2014. Ultrasound was performed on 68 patients with this type of injury, and early clots were found in nine patients, of whom only one developed retained hemothorax. We conclude that there is no direct relation between the occurrence of blood clots in the early hemothorax and the development of retained clotted hemothorax. Studies with large numbers of patients are required to demonstrate this association

Skeletal muscle inflammation and atrophy in heart failure.

Heart failure represents a systemic disease with profound effects on multiple peripheral tissues including skeletal muscle. Within the context of heart failure, perturbations in skeletal muscle physiology, structure, and function strongly contribute to exercise intolerance and the morbidity of this devastating disease. There is growing evidence that chronic heart failure imparts specific pathological changes within skeletal muscle beds resulting in muscle dysfunction and tissue atrophy. Mechanistically, systemic and local inflammatory responses drive critical aspects of this pathology. In this review, we will discuss pathological mechanisms that drive skeletal muscle inflammation and highlight emerging roles for distinct innate immune subsets that reside within damage muscle tissue focusing on the recently described embryonic and monocyte-derived macrophage lineages. Within this context, we will discuss how immune mechanisms can be differentially targeted to stimulate skeletal muscle inflammation, catabolism, fiber atrophy, and regeneration.

Vitamin D Levels Are Unrelated to the Severity of Respiratory Syncytial Virus Bronchiolitis Among Hospitalized Infants.

BACKGROUND: Vitamin D deficiency at birth has been reported as a risk factor for respiratory syncytial virus (RSV) lower respiratory tract infection during the first year of life. Limited data are available on whether an infant's vitamin D status is associated with the severity of acute RSV bronchiolitis. METHODS: Infants < 1 year of age and hospitalized with their first episode of RSV bronchiolitis were enrolled into the RSV Bronchiolitis in Early Life II cohort. We investigated the relationships between vitamin D status at enrollment and the following indicators of bronchiolitis severity: duration of hospitalization, lowest oxygen saturation measured during hospitalization, and bronchiolitis severity score. RESULTS: Among the 145 enrolled infants, the median (quartile 1 [Q1], Q3) serum 25-OH-VitD level was 36.8 (29.8, 42.3) ng/mL, with 14 infants (9.7%) having deficient serum vitamin D levels (25-OH-VitD <20 ng/mL). Vitamin D-deficient infants were younger than infants with 25-OH-VitD ≥ 20 ng/mL (2.8 vs 4.5 months, respectively; P = .04) and were less likely to consume infant's formula (42.9% vs 87.0%, respectively; P < .01). The following indicators of acute bronchiolitis severity did not differ between infants who were vitamin D-deficient and nondeficient: duration of hospitalization (P = .53), lowest oxygen saturation (P = .45), and bronchiolitis severity score (P = .97), even after adjusting for age, and for infant's formula consumption. CONCLUSIONS: Among this cohort of infants that were hospitalized for RSV bronchiolitis, vitamin D status at the time of bronchiolitis was not associated with indicators of acute bronchiolitis severity.

Deletion of macrophage Vitamin D receptor promotes insulin resistance and monocyte cholesterol transport to accelerate atherosclerosis in mice.

Intense effort has been devoted to understanding predisposition to chronic systemic inflammation because it contributes to cardiometabolic disease. We demonstrate that deletion of the macrophage vitamin D receptor (VDR) in mice (KODMAC) is sufficient to induce insulin resistance by promoting M2 macrophage accumulation in the liver as well as increasing cytokine secretion and hepatic glucose production. Moreover, VDR deletion increases atherosclerosis by enabling lipid-laden M2 monocytes to adhere, migrate, and carry cholesterol into the atherosclerotic plaque and by increasing macrophage cholesterol uptake and esterification. Increased foam cell formation results from lack of VDR-SERCA2b interaction, causing SERCA dysfunction, activation of ER stress-CaMKII-JNKp-PPARγ signaling, and induction of the scavenger receptors CD36 and SR-A1. Bone marrow transplant of VDR-expressing cells into KODMAC mice improved insulin sensitivity, suppressed atherosclerosis, and decreased foam cell formation. The immunomodulatory effects of vitamin D in macrophages are thus critical in diet-induced insulin resistance and atherosclerosis in mice.

Longitudinal changes in airway remodeling and air trapping in severe asthma.

RATIONALE AND OBJECTIVES: Previous cross-sectional studies have demonstrated that airway wall thickness and air trapping are greater in subjects with severe asthma than in those with mild-to-moderate asthma. However, a better understanding of how airway remodeling and lung density change over time is needed. This study aimed to evaluate predictors of airway wall remodeling and change in lung function and lung density over time in severe asthma. MATERIALS AND METHODS: Phenotypic characterization and quantitative multidetector-row computed tomography (MDCT) of the chest were performed at baseline and ∼2.6 years later in 38 participants with asthma (severe n = 24 and mild-to-moderate n = 14) and nine normal controls from the Severe Asthma Research Program. RESULTS: Subjects with severe asthma had a significant decline in postbronchodilator forced expiratory volume in 1 second percent (FEV1%) predicted over time (P < .001). Airway wall thickness measured by MDCT was increased at multiple airway generations in severe asthma compared to mild-to-moderate asthma (wall area percent [WA%]: P < .05) and normals (P < .05) at baseline and year 2. Over time, there was an increase in WA% and wall thickness percent (WT%) in all subjects (P = .030 and .009, respectively) with no change in emphysema-like lung or air trapping. Baseline prebronchodilator FEV1% inversely correlated with WA% and WT% (both P < .05). In a multivariable regression model, baseline WA%, race, and health care utilization were predictors of subsequent airway remodeling. CONCLUSIONS: Severe asthma subjects have a greater decline in lung function over time than normal subjects or those with mild-to-moderate asthma. MDCT provides a noninvasive measure of airway wall thickness that may predict subsequent airway remodeling.

Vascular calcification and aortic fibrosis: a bifunctional role for osteopontin in diabetic arteriosclerosis.

OBJECTIVE: Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)-/- mice fed a high-fat diet. METHODS AND RESULTS: OPN had no impact on high-fat diet-induced hyperglycemia, dyslipidemia, or body composition. However, OPN-/-;LDLR-/- mice exhibited an altered time-course of aortic calcium accrual-reduced during initiation but increased with progression-versus OPN+/+;LDLR-/- controls. Collagen accumulation, chondroid metaplasia, and mural thickness were increased in aortas of OPN-/-;LDLR-/- mice. Aortic compliance was concomitantly reduced. Vascular reexpression of OPN (SM22-OPN transgene) reduced aortic Col2A1 and medial chondroid metaplasia but did not affect atherosclerotic calcification, Col1A1 expression, collagen accumulation, or arterial stiffness. Dosing with the proinflammatory OPN fragment SVVYGLR upregulated aortic Wnt and osteogenic gene expression, increased aortic ß-catenin, and restored early-phase aortic calcification in OPN-/-;LDLR-/- mice. CONCLUSIONS: OPN exerts stage-specific roles in arteriosclerosis in LDLR-/- mice. Actions phenocopied by the OPN metabolite SVVYGLR promote osteogenic calcification processes with disease initiation. OPN limits vascular chondroid metaplasia, endochondral mineralization, and collagen accumulation with progression. Complete deficiency yields a net increase in arteriosclerotic disease, reducing aortic compliance and conduit vessel function in LDLR-/- mice.

Runx2 trans-activation mediated by the MSX2-interacting nuclear target requires homeodomain interacting protein kinase-3.

Runt-related transcription factor 2 (Runx2) and muscle segment homeobox homolog 2-interacting nuclear target (MINT) (Spen homolog) are transcriptional regulators critical for mammalian development. MINT enhances Runx2 activation of osteocalcin (OC) fibroblast growth factor (FGF) response element in an FGF2-dependent fashion in C3H10T1/2 cells. Although the MINT N-terminal RNA recognition motif domain contributes, the muscle segment homeobox homolog 2-interacting domain is sufficient for Runx2 activation. Intriguingly, Runx1 cannot replace Runx2 in this assay. To better understand this Runx2 signaling cascade, we performed structure-function analysis of the Runx2-MINT trans-activation relationship. Systematic truncation and domain swapping in Runx1:Runx2 chimeras identified that the unique Runx2 activation domain 3 (AD3), encompassed by residues 316-421, conveys MINT+FGF2 trans-activation in transfection assays. Ala mutagenesis of Runx2 Ser/Thr residues identified that S301 and T326 in AD3 are necessary for full MINT+FGF2 trans-activation. Conversely, phosphomimetic Asp substitution of these AD3 Ser/Thr residues enhanced activation by MINT. Adjacent Pro residues implicated regulation by a proline-directed protein kinase (PDPK). Systematic screening with PDPK inhibitors identified that the casein kinase-2/homeodomain-interacting protein kinase (HIPK)/dual specificity tyrosine phosphorylation regulated kinase inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), but not ERK, c-Jun N-terminal kinase, p38MAPK, or other casein kinase-2 inhibitors, abrogated Runx2-, MINT-, and FGF2-activation. Systematic small interfering RNA-mediated silencing of DMAT-inhibited PDPKs revealed that HIPK3 depletion reduced MINT+FGF2-dependent activation of Runx2. HIPK3 and Runx2 coprecipitate after in vitro transcription-translation, and recombinant HIPK3 recognizes Runx2 AD3 as kinase substrate. Furthermore, DMAT treatment and HIPK3 RNAi inhibited MINT+FGF2 activation of Runx2 AD3, and nuclear HIPK3 colocalized with MINT. HIPK3 antisense oligodeoxynucleotide selectively reduced Runx2 protein accumulation and OC gene expression in C3H10T1/2 cells. Thus, HIPK3 participates in MINT+FGF2 regulation of Runx2 AD3 activity and controls Runx2-dependent OC expression.