Anaerobic infections of the soft tissue and bones

Severe soft tissue infections, usually necrotizing, are associated with a mortality of 40-60% and with amputations where the bones and joints are involved. The anaerobic bacteria associated with these infections are usually present in patients with underlying predisposing conditions (diabetes, vascular problems, immunosuppression). They are in the majority polymicrobial, endogenous or exogenous. There are many clinical and laboratory characteristics to establish the diagnosis of the different forms of these infections. Treatment of necrotizing soft tissue and bone infections requires early and aggressive surgical debridment. Timing of diagnosis and surgery influence essentially the outcome. Colostomy can be helpful in cases of perineal involvement. Antibiotic covering (broad spectrum) is mandatory as well as the systemic support of the patient.     

Are synovial biopsies of diagnostic value?

Synovial tissue is readily accessible by closed needle or arthroscopic biopsy. These techniques provide adequate tissue for most diagnostic requirements. Examination of synovial tissue can assist in the diagnosis of some joint infections, and in several atypical or rare synovial disorders. Histological confirmation is not normally required for diagnosis of the common forms of inflammatory arthritis, including rheumatoid arthritis (RA). In patients with either established or early RA, immunohistological measures of inflammation in synovial tissue are associated with clinical measures of disease activity, may predict the clinical outcome, and change in response to treatment. Surrogate markers of disease activity and outcome that have been identified in synovial tissue include components of the cellular infiltrate, and several mediators of inflammation and matrix degradation. There is evidence that the very early introduction of disease-modifying therapy inhibits progressive structural damage maximally. Clinicians exploiting this 'window of opportunity' therefore require very early indicators of the diagnosis and outcome in patients who present with an undifferentiated inflammatory arthritis. Some immunohistological features have been described that distinguish patients who are likely to develop progressive RA and who might benefit most from early aggressive therapeutic intervention. In this regard, the inclusion of pharmacogenomic and proteomic techniques in the analysis of synovial tissue presents some exciting possibilities for future research.     

The Promher Study: An Observational Italian Study on Adjuvant Therapy for HER2-Positive,pT1a-b pN0 Breast Cancer

BackgroundThe management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients.MethodsData of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted.ResultsAmong 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p<0.001).ConclusionsThe majority of patients (66%) with pT1a-b pN0 HER2-positive breast cancer enrolled in this retrospective study received adjuvant systemic therapy with trastuzumab, whereas only 11% patients did not receive any adjuvant systemic therapy. The choice of treatment type seems to be mainly influenced by tumor size, proliferation index, hormone receptor status and age. The 5-year DFS probability was significantly higher for patients receiving adjuvant systemic therapy with trastuzumab compared with patients not receiving adjuvant systemic therapy or receiving adjuvant systemic therapy without trastuzumab.     

Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy

The lipodystrophy syndrome (adipose tissue redistribution and metabolic abnormalities) observed with highly active antiretroviral therapy (HAART) during human immunodeficiency virus (HIV) infection may be related to increased proinflammatory cytokine activity. We measured acute cytokine (TNF-alpha, IL-6, leptin), glycerol, and lactate secretion from abdominal subcutaneous adipose tissue (SAT), and systemic cytokine levels, in HIV-infected subjects with and without lipodystrophy (HIVL+ and HIVL-, respectively) and healthy non-HIV controls. Lipodystrophy was confirmed and characterized as adipose tissue redistribution in HIVL+ compared with HIVL- and controls, by dual-energy X-ray absorptiometry and by whole body MRI. TNF-alpha secretion from abdominal SAT and circulating levels of IL-6, soluble TNF receptors I and II, and insulin were elevated in HIVL+ relative to HIVL- and/or controls, particularly in HIVL+ undergoing HAART. In the HIV-infected group as a whole, IL-6 secretion from abdominal SAT and serum IL-6 were positively associated with visceral fat and were negatively associated with the relative amount of lower limb adipose tissue (P < 0.01). Decreased leptin and increased lactate secretion from abdominal SAT were specifically associated with HAART. In conclusion, increased cytokine secretion from adipose tissue and increased systemic proinflammatory cytokine activity may play a significant role in the adipose tissue remodeling and/or the metabolic abnormalities associated with the HIV-lipodystrophy syndrome in patients undergoing HAART.     

Leukotriene B4 Levels in Human Atherosclerotic Plaques and Abdominal Aortic Aneurysms

Background

Leukotriene B4 (LTB4) has been associated with the initiation and progression of atherosclerosis and abdominal aortic aneurysm (AAA) formation. However, associations of LTB4 levels with tissue characteristics and adverse clinical outcome of advanced atherosclerosis and AAA are scarcely studied. We hypothesized that LTB4 levels are associated with a vulnerable plaque phenotype and adverse clinical outcome. Furthermore, that LTB4 levels are associated with inflammatory AAA and adverse clinical outcome.

Methods

Atherosclerotic plaques and AAA specimens were selected from two independent databases for LTB4 measurements. Plaques were isolated during carotid endarterectomy from asymptomatic (n = 58) or symptomatic (n = 317) patients, classified prior to surgery. LTB4 levels were measured without prior lipid extraction and levels were corrected for protein content. LTB4 levels were related to plaque phenotype, baseline patient characteristics and clinical outcome within three years following surgery. Seven non-diseased mammary artery specimens served as controls. AAA specimens were isolated during open repair, classified as elective (n = 189), symptomatic (n = 29) or ruptured (n = 23). LTB4 levels were measured similar to the plaque measurements and were related to tissue characteristics, baseline patient characteristics and clinical outcome. Twenty-six non-diseased aortic specimens served as controls.

Results

LTB4 levels corrected for protein content were not significantly associated with histological characteristics specific for vulnerable plaques or inflammatory AAA as well as clinical presentation. Moreover, it could not predict secondary manifestations independently investigated in both databases. However, LTB4 levels were significantly lower in controls compared to plaque (p = 0.025) or AAA (p = 0.017).

Conclusions

LTB4 levels were not associated with a vulnerable plaque phenotype or inflammatory AAA or clinical presentation. This study does not provide supportive evidence for a role of LTB4 in atherosclerotic plaque destabilization or AAA expansion. However, these data should be interpreted with care, since LTB4 measurements were performed without prior lipid extractions.     

Epithelial cell proliferative activity and oral cancer progression

Accurate, predictive assessment of the behaviour and progression of oral cancers and precancers remains elusive in clinical practice. Archival tissue specimens from 10 previously treated patients with oral lesions of known clinical outcome (3 years post-treatment) were re-examined histopathologically, and proliferative cell labelling indices (LIs) determined for Ki67, cyclin A and histone mRNA cell cycle markers. While histone mRNA labelling ultimately proved unreliable, both Ki67 and cyclin A LIs demonstrated a clear trend for enhanced labelling to occur in increasingly dysplastic and neoplastic tissue, with particular emphasis on suprabasal labelling in abnormal tissue. Perhaps of greatest significance was the observation of increased LIs and suprabasal labelling in lesions with poor clinical outcome, such as patients developing recurrent disease or cervical lymph node metastasis. Measurement of cell proliferative activity in individual oral epithelial dysplastic lesions or invasive squamous cell carcinomas may thus provide unique, predictive information on clinical outcome.     

The role of oxidative stress in adult critical care

Oxidative stress defines an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants and scavenger enzymes. Evidence of massive oxidative stress is well established in adult critical illnesses characterized by tissue ischemia-reperfusion injury and by an intense systemic inflammatory response such as during sepsis and acute respiratory distress syndrome. Oxidative stress could exacerbate organ injury and thus overall clinical outcome. We searched MEDLINE databases (January 1966 to June 2005). For interventional studies, we accepted only randomized trials. Several small clinical trials have been performed in order to reduce oxidative stress by supplementation of antioxidants alone or in combination with standard therapies. These studies have reported controversial results. Newer large multicenter trials with antioxidant supplementation should be performed, considering administration at an early stage of illness and a wider population of critically ill patients.     

Vision-Related Quality of Life in Patients with Inactive HLA-B27–Associated-Spectrum Anterior Uveitis

We investigated the vision-related quality of life (VR-QOL) in patients with HLA-B27 associated anterior uveitis (AU). The study was conducted in 2012 at the ophthalmology department of the University Medical Center of Groningen. We included AU patients who were HLA-B27 positive and/or were diagnosed by a rheumatologist with an HLA-B27 associated systemic disease. Sixty-one of 123 (50%) adult patients participated. All patients filled-out the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25), Beck Depression Inventory (BDI-II), social support lists and an additional questionnaire for gathering general information. Medical records were reviewed for clinical characteristics. Analyses were conducted on various patient and ocular characteristics. We compared our NEI VFQ-25 scores with those previously found in the literature. Our main outcome measures were VR-QOL scores and their associations with various general patient and ocular characteristics. We found that the NEI VFQ-25 mean overall composite score was 88.9±8.8, which is relatively high, but lower than that found in a normal working population. The mean general health score was 47.4±20.8, which is lower than in patients with other ocular diseases. Patients with a systemic disease scored significantly lower on general health and VR-QOL, compared to patients without a systemic disease. Patients with a depression (6/59 (10%)) frequently had ankylosing spondylitis (5/6 patients) and they scored significantly worse on VR-QOL. We concluded that patients with HLA-B27 associated AU have a relatively high VR-QOL. However, the presence of a systemic disease is associated with lower VR-QOL and general health scores. In addition, depression is associated with a lower VR-QOL.     

Taming lupus-a new understanding of pathogenesis is leading to clinical advances

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the loss of tolerance to nuclear self antigens, the production of pathogenic autoantibodies and damage to multiple organ systems. Over the years, patients with SLE have been managed largely with empiric immunosuppressive therapies, which are associated with substantial toxicities and do not always provide adequate control of the disease. The development of targeted therapies that specifically address disease pathogenesis or progression has lagged, largely because of the complex and heterogeneous nature of the disease, as well as difficulties in designing uniform outcome measures for clinical trials. Recent advances that could improve the treatment of SLE include the identification of genetic variations that influence the risk of developing the disease, an enhanced understanding of innate and adaptive immune activation and regulation of tolerance, dissection of immune cell activation and inflammatory pathways and elucidation of mechanisms and markers of tissue damage. These discoveries, together with improvements in clinical trial design, form a platform from which to launch the development of a new generation of lupus therapies.     

Type I interferon in organ-targeted autoimmune and inflammatory diseases

A significant role for IFNα in the pathogenesis of systemic lupus erythematosus is well supported, and clinical trials of anti-IFNα monoclonal antibodies are in progress in this disease. In other autoimmune diseases characterized by substantial inflammation and tissue destruction, the role of type I interferons is less clear. Gene expression analysis of peripheral blood cells from patients with rheumatoid arthritis and multiple sclerosis demonstrate an interferon signature similar to but less intense than that seen in patients with lupus. In both of those diseases, presence of the interferon signature has been associated with more significant clinical manifestations. At the same time, evidence supports an anti-inflammatory and beneficial role of IFNβ locally in the joints of patients with rheumatoid arthritis and in murine arthritis models, and many patients with multiple sclerosis show a clinical response to recombinant IFNβ. As can also be proposed for type I diabetes mellitus, type I interferon appears to contribute to the development of autoimmunity and disease progression in multiple autoimmune diseases, while maintaining some capacity to control established disease - particularly at local sites of inflammation. Recent studies in both rheumatoid arthritis and multiple sclerosis suggest that quantification of type I interferon activity or target gene expression might be informative in predicting responses to distinct classes of therapeutic agents.     

Challenges in the Therapy of Chromoblastomycosis

Chromoblastomycosis (CBM) is an implantation mycosis mainly occurring in tropical and subtropical zones worldwide. If not diagnosed at early stages, patients with CBM require long-term therapy with systemic antifungals flanked by various physical treatment regimens. As in other neglected endemic mycoses, comparative clinical trials have not been performed for this disease; nowadays, therapy is mainly based on a few open trials and on expert opinions. Itraconazole, either as monotherapy or associated with other drugs, or with physical methods, is widely used. Recently, photodynamic therapy has been employed successfully in combination with antifungals in patients presenting with CBM. In the present paper, the most used therapeutic options against CBM are reviewed as well as the several factors that may have impact on the patient’s outcome.     

Interstitial lung diseases in children

Interstitial lung disease (ILD) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. These disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. Typical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ILD. Consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. The following diagnostic grouping is used to discuss the various causes of pediatric ILD: 1) exposure-related ILD; 2) systemic disease-associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. The outcome is highly variable with a mortality rate around 15%. An overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy.     

Genomic and proteomic determinants of outcome in patients undergoing thoracoabdominal aortic aneurysm repair

Thoracoabdominal aortic aneurysm repair, with its requisite intraoperative mesenteric ischemia-reperfusion, often results in the development of systemic inflammatory response syndrome, multiorgan dysfunction syndrome (MODS), and death. In the present study, an adverse clinical outcome following thoracoabdominal aortic aneurysm repair was identified by blood leukocyte genomic and plasma proteomic responses. Time-dependent changes in the expression of 146 genes from blood leukocytes were observed (p < 0.001). Expression of 138 genes (p < 0.001) and the concentration of seven plasma proteins discriminated between patients who developed MODS and those who did not, and many of these differences were evident even before surgery. These findings suggest that changes in blood leukocyte gene expression and plasma protein concentrations can illuminate pathophysiological processes that are subsequently associated with the clinical sequelae of systemic inflammatory response syndrome and MODS. These changes in gene expression and plasma protein concentrations are often observed before surgery, consistent with either a genetic predisposition or pre-existing inflammatory state.     

Non-coding RNAs in cancer-associated cachexia: clinical implications and future perspectives

Cachexia is a multifactorial syndrome characterized by skeletal muscle loss, with or without adipose atrophy, irreversible through nutritional support, in the context of systemic inflammation and metabolic disorders. It is mediated by inflammatory reaction and affects almost 50% of all cancer patients, due to prominent systemic inflammation associated with the disease. The comprehension of the molecular mechanisms that are implicated in cancer cachexia sheds light on its pathogenesis and lays the foundations for the discovery of new therapeutic targets and biomarkers. Recently, ncRNAs, like microRNAs as well as lncRNAs and circRNAs seem to regulate pathways that are implicated in cancer cachexia pathogenesis, as it has been observed in animal models and in cancer cachexia patients, highlighting their therapeutic potential. Moreover, increasing evidence highlights the involvement of circulating and exosomal ncRNAs in the activation and maintenance of systemic inflammation in cancer and cancer-associated cachexia. In that context, the present review focuses on the clinical significance of ncRNAs in cancer-associated cachexia.     

Autoantibody to DNA binding protein B as a novel serologic marker in systemic sclerosis

Systemic sclerosis is a systemic disease that is characterized by tissue fibrosis, small-vessel vasculopathy, and an autoimmune response associated with autoantibodies. We performed serological analysis of cDNA expression library (SEREX) to identify autoantibodies associated with systemic sclerosis. We identified 4 clones that react with sera of patients with SSc but not with those of healthy donors. These clones are phosphoglycerate mutase, centromere autoantigen C, U1 small nuclear ribonucleoprotein, and DNA binding protein B (dbpB). We chose to study autoantibody to DNA binding protein B. Immunoreactivity against recombinant dbpB was detected in 40.5% (15/37) of patients with SSc, 14.6% (6/41) of patents with systemic lupus erythematosus, 6.7% (1/15) of patients with rheumatoid arthritis, 0% (0/12) of patients with Sjogren syndrome, and 5.9% (1/17) of patients with polymyositis/dermatomyositis. The frequency of anti-dbpB was significantly higher in the SSc patients (15/37, 40.5%) compared to the healthy controls (3/41, 7.3%, p=0.0005 by chi(2) test). Eleven patients (11/20, 55%) with the diffuse cutaneous type of SSc had anti-dbpB and 4 patients (4/17, 23.5%) with the limited cutaneous type had anti-dbpB. The presence of anti-dbpB was significantly associated with the diffuse cutaneous type (p=0.00003 by chi(2) test). This is the first report to suggest that autoantibody to dbpB can be used as a serologic marker of systemic sclerosis.     

Clinical and Histopathological Features of Patients with Systemic Sclerosis Undergoing Endomyocardial Biopsy

BackgroundCardiac involvement in systemic sclerosis (SSc) is associated with a variable phenotype including heart failure, arrhythmias and pulmonary hypertension. The aim of the present study was to evaluate clinical characteristics, histopathological findings and outcome of patients with SSc and a clinical phenotype suggesting cardiac involvement.ConclusionsPatients with SSc and clinical signs of cardiac involvement presented with mildly impaired LVEF. Prognosis was poor with an event rate of 28% within 22.5 months FU and was associated with the degree of cardiac inflammation and fibrosis.     

Delirium subsindrómico en pacientes ancianos: revisión sistemática

In this systemic review, the articles published between1990 and November 2012 on subsyndromal delirium (SSD), and specifically those with reference to geriatric patients, were analysed. In SSD, symptoms from the three nuclear domains of delirium (cognitive, circadian and higher order thinking) are simultaneously present, with mild to moderate severity. Although the search for these clinical characteristics is a useful guide, there are no universally accepted diagnostic criteria for SSD. Regardless of the criteria used for diagnosis, SSD is persistently associated with poor functional and cognitive outcome, longer hospital stay, institutionalisation, and increased mortality. Studies are needed on the physiopathology, treatment and prevention in the field of SSD, which is a particularly important clinical condition in geriatric patients.     

Association of Angiopoietin-2 and Dimethylarginines with Complicated Course in Patients with Leptospirosis

Leptospirosis is one of the most relevant zoonosis worldwide and a potentially life-threatening infectious disease. While it is frequent in tropic regions, it is uncommon in European industrialized countries. Angiopoietin-2 (Angpt-2) and asymmetric and symmetric dimethylarginine (ADMA and SDMA) are markers of endothelial activation and systemic inflammation. These parameters have been studied recently in the context of sepsis and MODS showing potential to determine disease severity and outcome specific parameters like acute kidney injury (AKI) and survival. These biomarkers were measured in 13 patients with leptospirosis. High levels of Angpt-2 were statistically significant associated with a complicated clinical course with occurrence of AKI, Sepsis and intensive care unit treatment. ADMA was significantly associated with occurrence of AKI and ICU treatment whereas SDMA was associated with AKI. Therefore these endothelial markers may serve as additional tools for risk stratification in these patients.     

Nephrogenic Systemic Fibrosis in Denmark– A Nationwide Investigation

Background

Nephrogenic systemic fibrosis is a debilitating and painful disorder with an increased stimulation of the connective tissue in the skin and systemic tissues. The disease is associated with exposure to gadolinium-based contrast agent used in magnetic resonance imaging in patients with renal impairment.

Methods

The prevalence of nephrogenic systemic fibrosis has so far never been determined at a national level. In 2009, Denmark was the first country to design a guideline for the tracing of nephrogenic systemic fibrosis patients. The aim of this paper is to communicate the main findings of this quest.

Results

The outcome of the nationwide investigation revealed that Denmark had 65 patients with nephrogenic systemic fibrosis and thereby the highest prevalence of nephrogenic systemic fibrosis worldwide with 65 per 5.6 million inhabitants, or 12 per million.

Conclusions

The nationwide investigation in Denmark revealed the highest prevalence of NSF worldwide. This may be rooted in a high level of awareness of NSF both among doctors, politicians and, not least, the media, combined with the fact that a nationwide NSF investigation was initiated.