Interference of gadolinium dechelated from MR contrast agents by calcium signaling in neuronal cells of GnRH.

Contrast agents (CAs) used in magnetic resonance imaging (MRI) are produced by chelating the metal gadolinium (Gd) with organic ligand molecules to form stable complexes. But, Gd3+ may dissociate from the CAs and subsequently might become toxic to its environment. Besides toxicity, it might inhibit calcium channels on cell membranes and this action could be detrimental to the cells governing biological development. The aim of this study was to investigate the interference of Gd3+ dechelated from the CAs by calcium signaling in the neuronal cells of gonadotropin-releasing hormone (GnRH), regulating puberty, and sexual development. The study used the mouse GT1-7 cell line as a model system, and Fura-2 based calcium imaging for detecting the interruption of intracellular calcium transport by the extracellular presence of Gd3+ as released from the CAs; gadodiamide and gadoterate meglumine, when the cells were stimulated in vitro culture by exposure to melatonin.The CA gadoterate meglumine interfered minimally with the calcium signaling, and thus its use is preferable in standard MRI exams. The release of Gd3+ from gadodiamide was significant and becomes of great concern as it may impact the neurophysiology of the neuronal cells in general, and gonadotropin production in particular, even in normal patients without nephrogenic systemic fibrosis. The toxicity induced by the influx of dechelated Gd3+ in the neurons of GnRH would have significant implications for puberty and reproductive functions.

Role of intermittent pneumatic compression in the treatment of breast cancer-related lymphoedema: a randomized controlled trial.

OBJECTIVE: To evaluate the role of intermittent pneumatic compression in the treatment of breast cancer-related lymphoedema. DESIGN: Randomized controlled trial. SETTING: Physical medicine and rehabilitation clinic at a university hospital. SUBJECTS: Seventy-six patients with lymphoedema. INTERVENTIONS: Patients were allocated into Group 1 (complex decongestive treatment, n = 38) and Group 2 (complex decongestive treatment + intermittent pneumatic compression, n = 38). The complex decongestive treatment involved skin care, manual lymphatic drainage, compression bandaging, and exercise for 20 sessions. Group 2 additionally received intermittent pneumatic compression. MAIN MEASURES: Quantitative outcomes consisted of volumetric measures prior to and after the treatment. Clinical assessments included severity of pain, heaviness and tightness, disability, grip strength, and depression. RESULTS: Lymphoedema was similar at baseline, but treatments significantly reduced the excess volume (from 373 mL to 203 mL in Group 1 and 379.5 mL to 189.5 mL in Group 2). Percentage excess volumes (PEVs) decreased in both groups. The percentage reduction of excess volume was better in Group 2 than Group 1, but the intergroup difference was not significant. The clinical scores reflected improvements, but the heaviness and tightness read significantly lower in Group 2 than Group 1. CONCLUSION: Intermittent pneumatic compression seems to add no benefit when combined with complex decongestive treatment of lymphoedema, but, may be functional in reducing the sensations of heaviness and tightness for the patients with pitting oedema.

Characterization of tympanic cavity volume in newborns using computerized tomography scanning / Caracterización del volumen de la cavidad timpánica en recién nacidos usando tomografía computadorizada

This study reports tympanic cavity (TC) volume in newborns, which was missing in the literature. Ex vivo histology and computerized tomography (CT) scans were performed on temporal bone and data were analyzed in part using software developed in house. CT images with a slice thickness of 0.5 mm were obtained from 5 newborn cadavers and analyzed independently by two expert researchers. The border of the TC was delineated manually and measurement of area of interest was calculated on masked images. Then, the area measurements from all sections were added to estimate the total volume. The agreements between the histological and CT findings were then compared for accuracy, repeatability and reliability. The Dice and Jaccard similarity coefficient measures were used as a statistical validation metric to evaluate the assessor's performance in manual volume segmentation. Good assessor agreement was observed with average Dice values above 0.8 indicating that consistent and reliable volume measurements were feasible. The proposed protocol was shown to be accurate in calculating the TC volume, and thus can be used for computer-assisted presurgical planning or for diagnosing structural alterations in TC.

El objetivo fue determinar el volumen de la cavidad timpánica (CT) en recién nacidos, información no encontrada en la literatura. Se realizaron escaners a través de tomografia computadorizada (TC) y estudios histológicos en el hueso temporal; los datos se analizaron utilizando un software desarrollado en nuestra institución. Se obtuvieron imágenes de secciones de TC, de 0,5 mm de grosor, a partir de 5 cadáveres de recién nacidos, los que fueron analizados de forma independiente por dos investigadores expertos. El margen de los cortes de TC fue delineado manualmente y la medición del área de interés se estimó sobre imágenes ocultas. Después, se añadieron las mediciones de área de todas las secciones para estimar el volumen total. Las concordancias entre el estudio histológico y los hallazgos de la TC se compararon en cuanto a precisión, repetibilidad y confiabilidad. Se utilizaron las medidas de coeficiente de similitud de Jaccard y Dice como métrica de validación estadística para evaluar el desempeño del asesor en la medición manual del volumen. Se observó una buena correlación del evaluador con los valores medios de Dice, por encima de 0,8 indicando que es factible obtener mediciones coherentes y confiables de volumen. El protocolo propuesto ha demostrado ser preciso para calcular el volumen de la CT, y por lo tanto se puede utilizar para la planificación prequirúrgica asistida o para el diagnóstico de alteraciones estructurales en la CT.

S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers.

This study examined the value of blood marker S100A1 in detecting cardiotoxicity induced by chemotherapy agents; trastuzumab and lapatinib, in normal rat heart. The rats were divided into three groups: control (n = 8, no treatment), T (n = 8, one time ip treatment with 10 mg/kg trastuzumab) and L (n = 8, oral treatment with 100 mg/kg/day lapatinib for 7 days). The activities of oxidative stress parameters Malondialdehyde (MDA), Superoxide dismutase (SOD), Catalase (CAT) and Glutathione (GSH) were measured from the extracted cardiac tissues. The levels of troponinI and S100A1 expressions were measured from blood samples. All biomarkers responded to the treatments as they exhibited alterations from their normative values, validating the chemically induced cardiotoxicity. S100A1 expression attenuated significantly (75%), which made the sensitive detection of cardiotoxicity feasible. Assessment of cardiotoxicity with S100A1 may be a valuable alternative in clinical oncology of cancers in some organs such as breast and prostate, as they do not overexpress it to compete against.

In vivo nephroprotective efficacy of propolis against contrast-induced nephropathy.

PURPOSE: Contrast agents administered in diagnostic imaging or interventional procedures of clinical radiology may cause contrast-induced nephropathy (CIN). Preventive measures against CIN involve pharmaceutical pretreatments, such as N-acetylcystein (NAC) or calpain, but alternative medicines can also be helpful. This study aims to assess the prospects of a natural compound, propolis, as a potential nephroprotector against a specific contrast agent, diatrizoate. METHODS: In vivo experiments were performed on 35 male rats in five groups: control, diatrizoate alone, and pretreatments with propolis, NAC, or calpain one hour before diatrizoate administration. Three days later, blood and renal tissue samples were collected and quantitatively processed for determining induced changes in critical biomarkers malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), as well as serum creatinine and plasma urea. RESULTS: Diatrizoate increased creatinine (113%), urea (400%), and MDA (162%) levels and decreased GSH (-71%), SOD (-69%), GSH-Px (-77%), and CAT (-73%) levels. Evaluating the response of each pretreatment provided sufficient evidence that propolis was as effective as either NAC or calpain, but consistently more prominent in restoring the MDA, GSH, SOD, and GSH-Px levels close to their normal range. This outcome demonstrated the nephroprotective effect of propolis against CIN. CONCLUSION: Propolis protects renal tissue against toxicity, free radicals, and other adverse effects induced by diatrizoate. This function is most likely exerted through the antioxidant and antitoxic activities of propolis.

Susceptibility-Based Differentiation of Intracranial Calcification and Hemorrhage in Pediatric Patients.

Differential diagnosis of intracranial hemorrhage versus calcification on conventional magnetic resonance images (MRIs) is often challenging. Although computed tomography (CT) confirms calcification, phase information obtained during susceptibility-weighted imaging can be useful in distinguishing between 2 pathologies. Fourteen patients previously diagnosed to have hemorrhage or calcification with imaging were included in the study retrospectively. Phase shift values of hemorrhage and calcification were compared by using Student t test. The pathologies identified were tuberous sclerosis, Sturge-Weber syndrome, craniopharyngioma, congenital cytomegalovirus, subependymal hemorrhages, and hemorrhagic microembolic infarction. Calcifications appeared hypointense whereas hemorrhages were hyperintense on phase maps (left-handed magnetic resonance system). Statistical comparison of phase shift values yielded significant difference between hemorrhage versus calcification (P < .01). Phase maps were found to offer valuable data to differentiate 2 pathologies when used complementary to conventional magnetic resonance images. Considering the relatively higher risks of radiation exposure in children, susceptibility-weighted imaging with phase maps may help to waive radiation exposure from CT.

Iron accumulation in multiple sclerosis: an early pathogenic event.

Iron has been shown to accumulate in deep gray matter structures in many forms of multiple sclerosis (MS), but detecting its presence early in the disease course (e.g., clinically isolated syndrome [CIS]) has been less clear. Here, we review a recent study where MRI scanning at 7 T together with susceptibility mapping was performed to assess iron deposition in CIS and control subjects. Susceptibility indicative of iron deposition was found to be increased in the globus pallidus, caudate, putamen and pulvinar of CIS patients compared with controls. The findings suggest that iron deposition is a pathological change that occurs early in the development of MS. Identifying the mechanisms of iron accumulation and determining whether iron promotes pathogenesis in MS are important areas of future research.

Feasibility and merits of performing preclinical imaging on clinical radiology and nuclear medicine systems.

Aim. Researchers have limited access to systems dedicated to imaging small laboratory animals. This paper aims to investigate the feasibility and merits of performing preclinical imaging on clinical systems. Materials and Methods. Scans were performed on rat and mouse models of diseases or injuries on four radiology systems, tomosynthesis, computed tomography (CT), positron emission tomography/computed tomography (PET-CT), and Magnetic Resonance Imaging (MRI), based on the availability at the author's institute. Results. Tomosysthesis delineated soft tissue anatomy and hard tissue structure with superb contrast and spatial resolution at minimal scan time and effort. CT allowed high resolution volumetric visualization of bones. Molecular imaging with PET was useful for detecting cancerous tissue in mouse but at the expense of poor resolution. MRI depicted abnormal or intervened tissue at quality and resolution sufficient for experimental studies. The paper discussed limitations of the clinical systems in preclinical imaging as well as challenges regarding the need of additional gadgets, modifications, or upgrades required for longitudinally scanning animals under anesthesia while monitoring their vital signs. Conclusion. Clinical imaging technologies can potentially make cost-effective and efficient contributions to preclinical efforts in obtaining anatomical, structural, and functional information from the underlying tissue while minimally compromising the data quality in certain situations.

Loss of primary cilia upregulates renal hypertrophic signaling and promotes cystogenesis.

Primary cilia dysfunction alters renal tubular cell proliferation and differentiation and associates with accelerated cyst formation in polycystic kidney disease. However, the mechanism leading from primary ciliary dysfunction to renal cyst formation is unknown. We hypothesize that primary cilia prevent renal cyst formation by suppressing pathologic tubular cell hypertrophy and proliferation. Unilateral nephrectomy initiates tubular cell hypertrophy and proliferation in the contralateral kidney and provides a tool to examine primary cilia regulation of renal hypertrophy. Conditional knockout of the primary cilia ift88 gene leads to delayed, adult-onset renal cystic disease, which provides a window of opportunity to conduct unilateral nephrectomy and examine downstream kinetics of renal hypertrophy and cyst formation. In wild-type animals, unilateral nephrectomy activated the mTOR pathway and produced appropriate structural and functional hypertrophy without renal cyst formation. However, in ift88 conditional knockout animals, unilateral nephrectomy triggered increased renal hypertrophy and accelerated renal cyst formation, leading to renal dysfunction. mTOR signaling also increased compared with wild-type animals, suggesting a mechanistic cascade starting with primary ciliary dysfunction, leading to excessive mTOR signaling and renal hypertrophic signaling and culminating in cyst formation. These data suggest that events initiating hypertrophic signaling, such as structural or functional loss of renal mass, may accelerate progression of adult polycystic kidney disease toward end-stage renal disease.

Liver Kupffer cells control the magnitude of the inflammatory response in the injured brain and spinal cord.

The CNS inflammatory response is regulated by hepatic chemokine synthesis, which promotes leukocytosis and facilitates leukocyte recruitment to the site of injury. To understand the role of the individual cell populations in the liver during the hepatic response to acute brain injury, we selectively depleted Kupffer cells (KC), using clodronate-filled liposomes, and assessed the inflammatory response following a microinjection of IL-1beta into the rat brain or after a compression injury in the spinal cord. We show by immunohistochemistry that KC depletion reduces neutrophil infiltration into the IL-1beta-injected brain by 70% and by 50% into the contusion-injured spinal cord. qRT-PCR analysis of hepatic chemokine mRNA expression showed that chemokine expression in the liver after brain injury is not restricted to a single cell population. In non-depleted rats, CXCL-10, IL-1beta, CCL-2, and MIP-1alpha mRNAs were increased up to sixfold more than in KC depleted rats. However, CXCL-1 and MIP-1beta were not significantly affected by KC depletion. The reduction in chemokine mRNA expression by the liver was not associated with decreased neutrophil mobilisation as might have been expected. These findings suggest that in response to CNS injury, KC mediated mechanisms are responsible for increasing neutrophil entry to the site of CNS injury, but that neutrophil mobilisation is dependent on other non-KC mediated events. However, the suppression of KC activity may prevent secondary damage after acute brain injury.

High-resolution magnetic resonance imaging of the human median nerve.

OBJECTIVES: It is widely accepted that peripheral nerve repairs performed within 6 weeks of injury have much better outcomes than those performed at later dates. However, there is no diagnostic technique that can determine if a traumatic peripheral nerve injury requires surgical intervention in the early postinjury phase. The objective of this article was to determine whether novel, noninvasive magnetic resonance imaging techniques could demonstrate the microstructure of human peripheral nerves that is necessary for determining prognosis and determining if surgery is indicated following traumatic injury. METHODS: Ex vivo magnetic resonance imaging protocols were developed on a 9.4-T research scanner using spin-echo proton density and gradient-echo imaging sequences and a specially designed, inductively coupled radio frequency coil. These imaging protocols were applied to in situ imaging of the human median nerve in 4 fresh-frozen cadaver arms. RESULTS: Noninvasive high-resolution images of the human median nerve were obtained. Structures in the nerve that were observed included fascicles, interfascicular epineurium, perineurium, and intrafascicular septations. CONCLUSION: Application of these imaging techniques to clinical scanners could provide physicians with a tool that is capable of grading the severity of nerve injuries and providing indications for surgery in the early postinjury phase.

Elastography imaging of small animal oncology models: a feasibility study.

To test the feasibility of applying ultrasonic elastography on small animal oncology models, experiments were performed in vitro and in situ on murine mammary lesions induced exogenously by tumor cell line 66.3. In vitro studies involved three 1-week-old excised tumors embedded in a phantom block with ultrasonic properties similar to those of soft biologic tissues. In situ studies involved five mice whose bodies were embedded in pure gelatin blocks. The data were acquired from the blocks with a clinical scanner modified to have an automated compressor assembly and processed to construct the elastograms at various imaging planes within each block. The results were analyzed both qualitatively and quantitatively to assess the merits of the elastographic imaging and its limitations for in vivo serial studies of tumors in small animal oncology models.