The burden of comorbidity is associated with symptomatic polymicrobial urinary tract infection among institutionalized elderly.

BACKGROUND: Urinary tract infections (UTIs), often sustained by polymicrobial flora (p-UTIs), are a common finding among nursing home patients, and associated with adverse outcomes and increased healthcare costs. P-UTIs have been extensively studied with regard to microbiological aspects. However, little is known about the characteristics of the host. AIMS: The aim of this study is to verify to which extent comorbidity characterizes elderly nursing home patients with p-UTIs. METHODS: We enrolled 299 patients with culture-positive UTI consecutively admitted to the nursing home of the "Fondazione San Raffaele Cittadella della Carità", Taranto, Italy. P-UTI was diagnosed when two uropathogens were simultaneously isolated. The burden of comorbidity was quantified using the Charlson comorbidity score index. Logistic regression analysis was used to assess the adjusted association of the variables of interest with the presence of p-UTI. RESULTS: P-UTIs were detected in 118/299 (39%) patients. According to logistic regression, the presence of p-UTIs was independently associated with the Charlson index (OR 1.70; 95% CI 1.06-2.72; P = .026). This association remained also after excluding participants without urinary catheter (OR 1.88; 95% CI 1.13-3.11; P = .015). DISCUSSION: The presence of P-UTIs is associated with the burden of comorbidity, but not with individual diseases. CONCLUSIONS: Older nursing home patients with comorbidity should be screened for the presence of p-UTIs; further studies are needed to evaluate the impact of early detection and treatment of p-UTIs on the development of comorbidity.

Clinical validation of combined serological biomarkers for improved hepatocellular carcinoma diagnosis in 961 patients.

BACKGROUND: Alpha-fetoprotein (AFP), the only serological marker currently available for the detection of hepatocellular carcinoma (HCC), is unsatisfactory because of its poor sensitivity, as are other recently proposed markers. Therefore new biomarkers are badly needed. Squamous cell carcinoma antigen (SCCA), a serine protease inhibitor physiologically present in the skin, has recently been reported to be present in HCC patients, as also the immunocomplexed (IC) forms of SCCA and AFP: SCCAIC and AFPIC, respectively. METHODS: To determine the diagnostic accuracy of new serum biomarkers for the diagnosis of HCC a rapid, simple ELISA test was applied in 961 patients. Sensitivity and specificity were determined for each marker and for all the markers combined in detecting smaller and larger HCC versus liver cirrhosis. RESULTS: In smaller HCC, receiver operating characteristics analysis yielded the following AUC: AFP 0.714 (CI 95% 0.679-0.748), AFPIC 0.691 (CI95% 0.655-0.748), SCCA 0.703 (CI95% 0.667-0.736), SCCAIC 0.694 (CI 95% 0.659-0.728). SCCA was inversely correlated with size. The combined use of AFPIC, SCCA and SCCAIC in patients displaying low levels of AFP (<20 IU/mL) identified 25.6% HCC (186/725). CONCLUSION: This study suggests that the use of a combination of all these markers in clinical practice provides a non invasive and simple test that could increase the accuracy of HCC diagnosis.

The Burden of Comorbidity Is Associated with Antibiotic Resistance Among Institutionalized Elderly with Urinary Infection: A Retrospective Cohort Study in a Single Italian Nursing Home Between 2009 and 2014.

Urinary tract infections (UTIs), which are common among nursing home patients, are associated with adverse outcomes and increased healthcare costs. Antibiotic resistance is an emerging problem, associated with excess morbidity and mortality; it has been suggested that this condition might be more prevalent among subjects with comorbid conditions. The aim of this study was to assess the association, if any, of antibiotic resistance with the burden of comorbidity in elderly with UTIs. This retrospective study enrolled 299 patients with culture-positive UTI consecutively admitted to the nursing home of the "Fondazione San Raffaele Cittadella della Carità", Taranto, Italy, which includes 80 beds under the direction of two geriatricians. The burden of comorbidity was quantified using the Charlson comorbidity score index. Diagnosis of UTI was ascertained by urine culture. Antibiotic resistance was defined according to the European Centre for Disease Prevention and Control expert proposal. Logistic regression was used to assess the adjusted association of the variables of interest with the presence of antibiotic resistance. Antibiotic resistance was detected in 162/299 (54%) patients. In logistic regression, the presence of antibiotic resistance was independently associated with higher Charlson score, after adjusting (odds ratio = 1.06; 95% confidence interval = 1.01-1.10). Antibiotic resistance is highly prevalent among nursing home residents; it is associated with the burden of comorbidity, but not with single diseases. This association and its potential implications should be assessed in dedicated studies.

Antifibrogenic effect of IFN-alpha2b on hepatic stellate cell activation by human hepatocytes.

Liver fibrosis commonly occurs in patients with hepatitis C virus (HCV) infection as a consequence of the chronic liver damage, thus leading to the development of liver cirrhosis. When hepatic stellate cells (HSCs) become active, they play an essential role in liver fibrogenesis. In this study, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), commonly elevated in chronic C hepatitis, stimulate the production of matrix metalloprotease-9 (MMP-9) by human hepatocytes at a transcriptional and translational level, but the addition of recombinant interferon-alpha2b (rIFN-alpha2b) hampers this effect. Furthermore, a human HSC line is activated in vitro by incubation with human MMP-9 in the presence of collagen I, and this effect is blocked by the MMP inhibitor BB94. A similar activation was observed when incubating HSCs with conditioned medium of hepatocytes previously stimulated with IL-1beta and TNF-alpha but not when using conditioned medium of hepatocytes costimulated with IL-1beta or TNF-alpha together with rIFN-alpha2b. In conclusion, our results show that hepatocytes stimulated by inflammatory cytokines participate in the activation of HSCs via MMP-9 production and that antiviral therapy modulates such activation.

Clinical role of serum and tissue matrix metalloprotease-9 expression in chronic HCV patients treated with pegylated IFN-alpha2b and ribavirin.

In chronic hepatitis C, the main goal of antiviral therapies is to block viral replication and to slow down the development of fibrosis. In this study, a decrease in matrix metalloprotease-9 (MMP-9) but not of MMP-2 and the tissue inhibitors of MMP (TIMP-1 and TMP-2) was observed in the plasma of chronic hepatitis C patients at the end of the follow-up period after ribavirin plus interferon-alpha2b (PEG-IFN-alpha2b) treatment in sustained virologic responders but not in nonresponders. Consistently, similar results are observed by immunofluorescence and real-time PCR in tissue specimens collected before and after therapy from the same patients in whom both Kupffer cells and hepatocytes express MMP-9. In conclusion, our results show that MMP-9 decreases in responder patients both in the serum and in the liver after therapy. Further studies are needed to investigate this new possible therapeutic activity of PEG-IFN-alpha2b.

The effect of bosentan on matrix metalloproteinase-9 levels in patients with systemic sclerosis-induced pulmonary hypertension.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease that can potentially involve all tissues and organs of the human body. Based on the extent of the disease and organ involvement, different subsets of patients and organ involvement, different subsets of patients have been identified and several classifications proposed have been identified and several classifications proposed aiming to better stratify affected patients. The occurrence aiming to better stratify affected patients. The occurrence of pulmonary arterial hypertension (PAH), characterized of pulmonary arterial hypertension (PAH), characterized by altered tissue remodelling of the entire vessel wall, is the most severe complication that influences prognosis and survival. The molecular basis underlying the vascular damage is not yet known, but a family of enzymes named matrix metalloproteinases (MMPs), with a proteolytic activity towards several extra-cellular matrix (ECM) components, is likely to be involved. Recently, a dual inhibitor of endothelin-1, bosentan, has been successfully evaluated in clinical trials in PAH patients. RESEARCH DESIGN AND METHOD: The aim of this study is to investigate the expression of MMP-2 and MMP-9 in the serum of different subsets of SSc patients, and in patients treated with bosentan. Thirty-five Caucasian patients with SSc were enrolled in the study, 12 of whom were found to have isolated PAH assessed by Doppler echocardiography. Eight patients fully met the inclusion criteria and were eligible for therapy with bosentan given at the dosage of 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily for 50 weeks(15). The remaining patients (4/12) initiated bosentan therapy for a few weeks and, therefore, were considered at the baseline level only. Serum samples were analysed by gelatine zymography. RESULTS: The results suggest that MMP-9 but not MMP-2 is differently expressed according to the degree of organ involvement. In particular, MMP-9 serum levels are significantly decreased in PAH with respect to other subsets of SSc patients. Moreover, in bosentan-treated patients, after 12 months of therapy MMP-9 significantly (p < 0.05) increased and correlated with an improved clinical outcome, as measured by the '6-minutes walking' test. CONCLUSIONS: This is the first time that MMP-9 serum levels are reported to be down-regulated in PAH patients and up-regulated following bosentan treatment. Whether MMP-9 has a pathogenetic role in the vascular damage observed in PAH patients or it is a marker of bosentan effectiveness is not yet known. However, MMP-9 may be an important molecule that needs further investigation in SSc patients to better define its role.

Laminin-5 chains are expressed differentially in metastatic and nonmetastatic hepatocellular carcinoma.

PURPOSE: The purpose of this work was to study the expression of the extracellular matrix protein laminin-5 (Ln-5) in hepatocellular carcinoma (HCC), which is the fifth most frequent cancer and the third most common cause of tumor-related death in the world. The occurrence of metastasis is the main problem in HCC patients. Ln-5 is an extracellular matrix component that promotes adhesion and migration; it is present at the basement membrane and has recently been associated with cancer metastasis. Although Ln-5 has been shown to promote motility and scatter of rat liver cells, it has never been found in the liver. EXPERIMENTAL DESIGN: We studied the expression and localization of the alpha3, beta3, and gamma2 chains of Ln-5 in 40 HCC patients. We analyzed tissue samples collected from the HCC primary nodule and from peritumoral and metastatic tissues. The presence of Ln-5 was investigated by immunohistochemistry, reverse transcription-PCR, and Northern blot analysis. The clinical outcome of the patients was evaluated over a 4-year follow-up period. RESULTS: This study provides the first report that Ln-5 is present in the HCC primary nodule, but not in normal or peritumoral cirrhotic tissues. In particular, the gamma2 chain is strongly associated with the occurrence of metastasis (96%; P < 0.001) and with worse prognosis. In peritumoral tissues, Ln-5 has been detected along the advancing edge of the metastatic nodule. CONCLUSIONS: Ln-5 is associated with a more metastatic phenotype of HCC, and its detection could be an important finding both as an unfavorable prognostic factor and as a diagnostic marker for detecting micrometastasis in peritumoral tissues.

Occurrence of portal vein tumor thrombus in hepatocellular carcinoma affects prognosis and survival. A retrospective clinical study of 150 cases.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. Despite improvements in diagnostic and therapeutic interventions, prognosis and survival are still poor. To identify factors influencing survival, we retrospectively examined 150 consecutive patients with HCC from the time of first diagnosis of cirrhosis to death. In a multivariate analysis, we found that patients with larger HCC lesions had shorter survival, while other pathologic features had no predictive value. The most important and reliable prognostic factor was the occurrence of tumor thrombus of the portal vein (P<0.01). Child's stage of underlying liver disease was relevant only in the univariate, but not in the multivariate analysis. The survival of patients with HCC is mainly affected by the biological ability of cancer cells to invade surrounding tissue and vessels. More studies are needed to elucidate the mechanisms that modulate tumor cell motility, in order to design more effective therapies.

Carbapenem resistance and mortality in institutionalized elderly with urinary infection.

OBJECTIVES: The emergence of antibiotic-resistant urinary pathogens represents a public health care concern. We aimed to detect antibiotic-resistance in elderly nursing home residents with urinary tract infection (UTI) and to assess the impact of carbapenem resistance on mortality. METHODS: This cohort study of 196 patients with UTI confirmed by a positive urine culture was conducted in a nursing home in Italy. Data on 6-month mortality was obtained by nursing home records and confirmed by death certificates. Diagnosis of UTI was ascertained by urine culture. Antibiotic resistance was defined according to antibiograms performed by the same laboratory. Cox regression analysis was used to assess the adjusted association between carbapenem resistance and 6-month mortality. RESULTS: Carbapenem resistance was found in 39/196 (20%) patients. After adjusting for potential confounders, carbapenem resistance was associated in Cox regression modeling with 6-month mortality (relative risk = 2.79; 95% confidence interval = 1.17-6.70; P = .021). CONCLUSIONS: In elderly in-patients, UTI from carbapenem-resistant germs is an independent risk factor for 6-month mortality, irrespective of the etiologic agent. Further studies are needed to clarify the mechanisms underlying this association.

Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world and a common occurrence in patients with liver cirrhosis in western and North American countries. Ultrasound screening is a powerful technique for HCC diagnosis, whereas the only available serologic test, alpha-fetoprotein, has poor reliability. It has been reported that the squamous cell carcinoma antigen (SCCA) is overexpressed in HCC tissue. In our study, the expression of SCCA was investigated in tumoral and peritumoral tissues and in the serum of 52 HCC patients, as well as in the serum of 48 cirrhotic patients. The results show that SCCA expression is much stronger in the tumoral than in the peritumoral tissue of HCC. Moreover, it is also evident in metastatic nodules present in the peritumoral tissue. SCCA serum levels were significantly higher in HCC samples than in cirrhotic samples. However, no correlation was found between SCCA expression and the HCC histologic degree, nor did SCCA expression correlate with tumor size, presence of metastasis or clinical outcome. In conclusion, in HCC patients, the SCCA antigen could represent a useful marker for the detection of micro-metastasis in the tissues and for large-scale screening of serum in patients at risk.

SCCA antigen combined with alpha-fetoprotein as serologic markers of HCC.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Because of its increased incidence in the last decade and the estimated further increase in the next 2 decades, HCC is arousing great interest. In Europe and North America, it commonly develops on cirrhotic livers, and surveillance programs have therefore been suggested to identify early HCC, at a stage when it remains suitable for surgical therapy and has a better clinical outcome. The only serologic marker used in clinical practice is alpha-fetoprotein (alpha-FP), but its sensitivity is poor. In our study, 120 patients with HCC and 90 patients with liver cirrhosis were investigated. We report for the first time to our knowledge that as a marker of HCC, the squamous cell carcinoma (SCCA) antigen has high sensitivity (84.2%) but low specificity (48.9%). However, the combination of alpha-FP and SCCA yielded a correct serologic diagnosis in 90.83% of the HCC patients. A small percentage of patients remain undetected, likely because of the low specificity of SCCA. In conclusion, the combined use of alpha-FP and SCCA antigen represents a more powerful tool for the serologic detection of HCC.

Gelatinase expression at positive patch test reactions.

Matrix metalloproteases (MMPs) are proteolytic enzymes involved in tissue remodelling and extracellular matrix (ECM) turnover. They are secreted in a latent form and activated at the cellular surface by a membrane type-1 MMP (MT1-MMP) and a tissue inhibitor of MMP-2 (TIMP-2) that is also responsible for striking a balance between the proteolytic enzymes and TIMP-2. In allergic contact dermatitis (ACD) patients, MMP-2 and MMP-9, two members of the MMPs family, were increased during the challenge phase, in involved but not uninvolved skin. In contrast, TIMP-2 was more evident in uninvolved than involved skin, while no differences were observed with regard to MT1-MMP staining. Comparing the serum of ACD patients with that of healthy subjects, these differences were not observed. These data suggest that MMP-2 and MMP-9 could play a role in the mechanisms inducing alterations of the epidermal architecture, and in the pathogenesis of the lesions.

Transforming growth factor-beta1 triggers hepatocellular carcinoma invasiveness via alpha3beta1 integrin.

Metastasis occurrence in the course of hepatocellular carcinoma (HCC) severely affects prognosis and survival. We have shown that HCC invasive cells express alpha3beta1-integrin whereas noninvasive cells do not. Here we show that transforming growth factor (TGF)-beta1 stimulates alpha3-integrin expression at a transcriptional level in noninvasive HCC cells, causing transformation into a motile and invasive phenotype. Such activities are inhibited by neutralizing anti-alpha3- but not anti-alpha6-integrin monoclonal antibodies. HCC invasive cells secrete abundant levels of active TGF-beta1 in comparison with noninvasive cells, but in the latter, addition of active matrix metalloproteinases-2 increases the concentration of active TGF-beta1. In this way, the cells express alpha3-integrin at a transcriptional level and acquire motility on Ln-5. By contrast, an anti-TGF-beta1-neutralizing antibody reduces alpha3-integrin expression and the invasive ability of HCC invading cells. In HCC patients, TGF-beta1 serum concentrations and alpha3-integrin expression are strongly correlated. The integrin, absent in normal and peritumoral liver parenchyma, is abundantly expressed in HCC primary and metastatic tissue. In particular, patients with metastasis show higher levels of TGF-beta1 serum concentrations and stronger expression of TGF-beta1 and alpha3-integrin in HCC tissues. In conclusion, TGF-beta1 may play an important role in HCC invasiveness by stimulating alpha3-integrin expression, and could therefore be an important target for new therapies.

Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma.

An imbalance between the proteolytic activity of matrix metalloproteinase-2 (MMP-2) and the tissue inhibitor of MMP-2 (TIMP-2) is responsible for degradation of extracellular matrix (ECM) components and plays a critical role in tumor invasion and in metastasis formation. The occurrence of intra-hepatic metastasis, which severely affects prognosis and long-term survival, is commonly observed in the course of hepatocellular carcinoma (HCC). We investigated the expression of MT1-MMP in tissues, whereas both MMP-2 and TIMP-2 were evaluated in the sera and tissues (primary and metastatic nodules) of HCC patients with and without metastasis, whose clinical outcome was followed over a 2-year period. MT1-MMP expression was similar among primary nodule tissues of patients with and without metastasis. Serum and tissue levels of MMP-2 were not statistically different between patients with and without metastasis, but MMP-2 was concentrated at the invasive edge of the metastatic tissue. On the contrary, serum and tissue levels of TIMP-2 were significantly higher in HCC patients without metastasis than in those with. This situation was not only observed in the primary HCC tissues, but also in the metastatic nodules. These results correlate with the clinical outcome, because more than 90% of the patients with high levels of TIMP-2 were still alive after 2 years, whereas less than 30% with low levels of TIMP-2 had survived. Furthermore, we found a strict correlation between tissue and serum levels of TIMP-2, this suggesting that a MMP-2/TIMP-2 imbalance and in particular TIMP-2 levels, could represent an important prognostic factor in patients with HCC.

Gelatinase levels in male and female breast cancer.

Breast cancer is a common disease in females but very rare in males, in whom it shows a more metastatic behavior, and a worse prognosis. Matrix metalloprotease-2 (MMP-2) and MMP-9 are proteolytic enzymes balanced by tissue inhibitor of MMP-2 (TIMP-2), commonly involved in cancer metastasis. This is the first study on gelatinolytic activity in male breast cancer patients, compared to that in female patients. In cancer tissues, both gelatinases were more expressed than in normal samples, being and more concentrated in male than in female patients. TIMP-2 levels were slightly increased in normal compared to those in cancer tissues and more concentrated in males than in females. Immunostaining showed that in male cancer tissues MMP-2 and MMP-9 staining was more intense and diffuse than in female cancer tissues, while no differences were observed regarding TIMP-2. In conclusion, the increased expression of gelatinases in male breast cancer patients together with anatomical features might explain the high tendency toward metastasis and the worse prognosis.