Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome

Although inflammation is a physiologic response designed to protect us from infection, when unchecked and ongoing it may cause substantial harm. Both chronic heart failure (CHF) and chronic kidney disease (CKD) are known to cause elaboration of several pro-inflammatory mediators that can be detected at high concentrations in the tissues and blood stream. The biologic sources driving this chronic inflammatory state in CHF and CKD are not fully established. Traditional sources of inflammation include the heart and the kidneys which produce a wide range of pro-inflammatory cytokines in response to neurohormones and sympathetic activation. However, growing evidence suggests that non-traditional biomechanical mechanisms such as venous and tissue congestion due to volume overload are also important as they stimulate endotoxin absorption from the bowel and peripheral synthesis and release of pro-inflammatory mediators. Both during the chronic phase and, more rapidly, during acute exacerbations of CHF and CKD, inflammation and congestion appear to amplify each other resulting in a downward spiral of worsening cardiac, vascular, and renal functions that may negatively impact patients’ outcome. Anti-inflammatory treatment strategies aimed at attenuating end organ damage and improving clinical prognosis in the cardiorenal syndrome have been disappointing to date. A new therapeutic paradigm may be needed, which involves different anti-inflammatory strategies for individual etiologies and stages of CHF and CKD. It may also include specific (short-term) anti-inflammatory treatments that counteract inflammation during the unsettled phases of clinical decompensation. Finally, it will require greater focus on volume overload as an increasingly significant source of systemic inflammation in the cardiorenal syndrome.     

Parry Romberg Syndrome associated with chronic facial pain

Parry Romberg Syndrome (PRS) is a rare condition of unknown cause and pathophysiology. It is characterized by progressive facial hemiatrophy, and neurological abnormalities are found in 20% of cases. We describe a 50-year-old woman with PRS and severe neurological involvement (lateralised epileptic seizure activity and facial pain refractory to medication). Pain intensity and frequency was reduced and control of epileptic crises was improved using levetiracetam as an additional therapy. In previous published cases associated with facial pain, the most frequent diagnoses were migraine and trigeminal neuralgia. Our findings suggest that in this patient PRS-related persistent pain has peculiar features possibly attributed to the underlying musculoskeletal abnormalities.     

In vivo monitoring of the bone healing process around different titanium alloy implant surfaces placed into fresh extraction sockets

Objectives

Increasing surface roughness and coating with tricalcium phosphate of titanium and titanium alloy implants has been proposed to provide better rates of osseointegration. However, how these changes in surface topography and chemistry influence the osseointegration process of immediate implants placed in fresh extraction sockets is unclear. This study investigated the influence of three clinically employed implant surfaces on the early bone healing events in vivo.

Methods

Machined smooth implants were milled from grade 5 Ti6Al4V titanium. Surfaces were moderately roughened by grit blasting, which were then coated with tricalcium phosphate. Implants were placed into freshly extracted incisor sockets of mandibles of normal Wistar rats and left for 1, 3 and 9 weeks. Healing bone tissue around the implants was examined by histochemistry and immunocytochemistry to localise PCNA proliferative cells, and osteoblast differentiation markers osteopontin and osteocalcin. Positive synthesising cells were counted using image analysis.

Results

Histology indicated no differences in the amount or pattern of bone formation within the healing tissue surrounding the different implant surfaces. Bone healing occurred predominantly on exposed bone surfaces (distance osteogenesis) and not on the implant surface (contact osteogenesis). No differences were observed in the number or timing of PCNA, osteopontin and osteocalcin positive cells within the bone healing tissue around each of the implant analysed.

Conclusion

For immediately placed implants, the surface modifications investigated appeared to have little influence on the activity of bone forming cells surrounding the implant, probably due to the high level of distance osteogenesis seen within this scenario.

Clinical significance

For immediate placement of implants into fresh extraction sockets, titanium implants with roughened surfaces and coating with tricalcium phosphate have negligible influence in accelerating the early bone healing events of osseointegration.     

Basal Cell Carcinoma of the Nipple in a Male Patient: A Particular Case Report

Basal cell carcinoma (BCC) is a common skin cancer worldwide. However, BCC of the nipple and areola complex is rare. Men are more affected than women. Most of the cases were treated with simple excision. We report a case of BCC of the right nipple–areola complex in a 75‐year‐old man, treated with Mohs surgery and simple mastectomy.     

BOLD fMRI integration into radiosurgery treatment planning of cerebral vascular malformations

Functional magnetic resonance imaging (fMRI) is used to distinguish areas of the brain responsible for different tasks and functions. It is possible, for example, by using fMRI images, to identify particular regions in the brain which can be considered as "functional organs at risk" (fOARs), i.e., regions which would cause significant patient morbidity if compromised. The aim of this study is to propose and validate a method to exploit functional information for the identification of fOARs in CyberKnife (Accuray, Inc., Sunnyvale, CA) radiosurgery treatment planning; in particular, given the high spatial accuracy offered by the CyberKnife system, local nonrigid registration is used to reach accurate image matching. Five patients affected by arteriovenous malformations (AVMs) and scheduled to undergo radiosurgery were scanned prior to treatment using computed tomography (CT), three-dimensional (3D) rotational angiography (3DRA), T2 weighted and blood oxygenation level dependent echo planar imaging MRI. Tasks were chosen on the basis of lesion location by considering those areas which could be potentially close to treatment targets. Functional data were superimposed on 3DRA and CT used for treatment planning. The procedure for the localization of fMRI areas was validated by direct cortical stimulation on 38 AVM and tumor patients undergoing conventional surgery. Treatment plans studied with and without considering fOARs were significantly different, in particular with respect to both maximum dose and dose volume histograms; consideration of the fOARs allowed quality indices of treatment plans to remain almost constant or to improve in four out of five cases compared to plans with no consideration of fOARs. In conclusion, the presented method provides an accurate tool for the integration of functional information into AVM radiosurgery, which might help to minimize undesirable side effects and to make radiosurgery less invasive.     

Multispectral imaging and artificial neural network: mimicking the management decision of the clinician facing pigmented skin lesions

Various instruments based on acquisition and elaboration of images of pigmented skin lesions have been developed in an attempt to in vivo establish whether a lesion is a melanoma or not. Although encouraging, the response of these instruments, e.g. epiluminescence microscopy, reflectance spectrophotometry and fluorescence imaging, cannot currently replace the well-established diagnostic procedures. However, in place of the approach to instrumentally assess the diagnosis of the lesion, recent studies suggest that instruments should rather reproduce the assessment by an expert clinician of whether a lesion has to be excised or not. The aim of this study was to evaluate the performance of a spectrophotometric system to mimic such a decision. The study involved 1794 consecutively recruited patients with 1966 doubtful cutaneous pigmented lesions excised for histopathological diagnosis and 348 patients with 1940 non-excised lesions because clinically reassuring. Images of all these lesions were acquired in vivo with a multispectral imaging system. The data set was randomly divided into a train (802 reassuring and 1003 excision-needing lesions, including 139 melanomas), a verify (464 reassuring and 439 excision-needing lesions, including 72 melanomas) and a test set (674 reassuring and 524 excision-needing lesions, including 76 melanomas). An artificial neural network (ANN(1)) was set up to perform the classification of the lesions as excision-needing or reassuring, according to the expert clinicians' decision on how to manage each examined lesion. In the independent test set, the system was able to emulate the clinicians with a sensitivity of 88% and a specificity of 80%. Of the 462 correctly classified as excision-needing lesions, 72 (95%) were melanomas. No major variations in receiver operating characteristic curves were found between the test and the train/verify sets. On the same data set, a further artificial neural network (ANN(2)) was then architected to perform classification of the lesions as melanoma or non-melanoma, according to the histological diagnosis. Having set the sensitivity in recognizing melanoma to 95%, ANN(1) resulted to be significantly better in the classification of reassuring lesions than ANN(2). This study suggests that multispectral image analysis and artificial neural networks could be used to support primary care physicians or general practitioners in identifying pigmented skin lesions that require further investigations.     

Nonredundant roles of antibody,cytokines, and perforin in the eradication of established Her-2/neu carcinomas

Since the mechanisms by which specific immunity destroys Her-2/neu carcinoma cells are highly undetermined, these were assessed in BALB/c mice vaccinated with plasmids encoding extracellular and transmembrane domains of the protein product (p185(neu)) of the rat Her-2/neu oncogene shot into the skin by gene gun. Vaccinated mice rejected a lethal challenge of TUBO carcinoma cells expressing p185(neu). Depletion of CD4 T cells during immunization abolished the protection, while depletion of CD8 cells during the effector phase halved it, and depletion of polymorphonuclear granulocytes abolished all protection. By contrast, Ig mu-chain gene KO mice, as well as Fcgamma receptor I/III, beta-2 microglobulin, CD1, monocyte chemoattractant protein 1 (MCP1), IFN-gamma, and perforin gene KO mice were protected. Only mice with both IFN-gamma and perforin gene KOs were not protected. Although immunization also cured all BALB/c mice bearing established TUBO carcinomas, it did not cure any of the perforin KO or perforin and IFN-gamma KO mice. Few mice were cured that had knockouts of the gene for Ig mu-chain, Fcgamma receptor I/III, IFN-gamma, or beta-2 microglobulin. Moreover, vaccination cured half of the CD1 and the majority of the MCP1 KO mice. The eradication of established p185(neu) carcinomas involves distinct mechanisms, each endowed with a different curative potential.