The effect of sophorolipids against microbial biofilms on medical-grade silicone.

Recent medical strategies rely on the search for effective antimicrobials as surface coatings to prevent and treat infections in humans and animals. Biosurfactants have recently been shown to have properties as antiadhesive and antibiofilm agents. Sophorolipids in particular are biosurfactant molecules known to act as therapeutic agents. This study aimed to evaluate antimicrobial properties of sophorolipids in medical-grade silicone discs using strains of clinical relevance. Sophorolipids were produced under fed batch conditions, ESI-MS analyses were carried out to confirm the congeners present in each formulation. Three different products were obtained SLA (acidic congeners), SL18 (lactonic congeners) and SLV (mixture of acidic and lactonic congeners) and were tested against Staphylococcus aureus ATCC 6538, Pseudomonas aeruginosa ATCC 10145 and Candida albicans IHEM 2894. All three congener mixtures showed a biofilms disruption effect (> 0.1 % w/v) of 70 %, 75 % and 80 % for S. aureus, P. aeruginosa and C. albicans, respectively. On pre-coated silicone discs, biofilm formation of S. aureus was reduced by 75 % using SLA 0.8 % w/v. After 1.5 h the inhibition of C. albicans attachment was between 45-56 % whilst after 24 h incubation the percentage of inhibition for the cell attachment increased to 68-70 % when using SLA 0.8 % w/v. Finally, in co-incubation experiments SLA 0.05 % w/v significantly reduced the ability of S. aureus and C. albicans to form biofilms and to adhere to surfaces by 90-95 % at concentrations between 0.025-0.1 % w/v. In conclusion sophorolipids significantly reduced the cell attachment of both tested strains which suggests that these molecules could have a potential role as coating agents on medical grade silicone devices for the preventions of Gram positive bacteria and yeast infections.

Evaluation of the Profile and Mechanism of Neurotoxicity of Water-Soluble [Cu(P)4]PF6 and [Au(P)4]PF6 (P = thp or PTA) Anticancer Complexes.

[Cu(thp)4]PF6, [Cu(PTA)4]PF6, [Au(thp)4]PF6 and [Au(PTA)4]PF6 are phosphane (thp = tris(hydroxymethyl)phosphane; PTA = 1,3,5-triaza-7-phosphaadamantane) copper(I) and gold(I) water-soluble complexes characterized by high anticancer activity in a wide range of solid tumors, often able to overcome drug resistance of platinum-based compounds. For these reasons, they have been proposed as a valid alternative to platinum-based chemotherapeutic drugs (e.g., cisplatin and oxaliplatin). In vitro experiments performed on organotypic cultures of dorsal root ganglia (DRG) from 15-day-old rat embryos revealed that copper-based compounds were not neurotoxic even at concentrations higher than the IC50 obtained in human cancer cells while [Au(PTA)4]PF6 was neurotoxic at lower concentration than IC50 in cancer cell lines. The ability of these compounds to hinder the proteasome machinery in DRG neurons was tested by fluorimetric assay showing that the non-neurotoxic copper-based complexes do not inhibit proteasome activity in DRG primary neuron cultures. On the contrary, the neurotoxic complex [Au(PTA)4]PF6, induced a significant inhibition of proteasome activity even at concentrations lower than the IC50 in cancer cells. The proteasome inhibition induced by [Au(PTA)4]PF6 was associated with a significant increase in α-tubulin polymerization that was not observed following the treatment with copper-based compounds. Uptake experiments performed by atomic absorption spectrometry showed that both copper-based complexes and [Au(PTA)4]PF6 are internalized in neuron cultures. In vitro and in vivo preliminary data confirmed copper-based complexes as the most promising compounds, not only for their anticancer activity but also concerning the peripheral neurotoxicity profile.

High Prevalence of Malnutrition among Elderly Veterans in Home Based Primary Care.

INTRODUCTION: Elderly Veterans enrolled in VA Home Based Primary Care (HBPC) programs suffer from many diseases including malnutrition. Nutrition screening tools exist in the VA system but they are inconsistently utilized across ambulatory care programs and are neither research validated nor comparable with non-VA populations. The Mini-Nutritional Assessment short-form (MNA-SF) has been validated in international studies in a variety of settings. The primary aim of this study was to find the prevalence of malnutrition among Veterans enrolled in HBPC programs. The secondary objective was to determine the feasibility of adopting a validated nutrition screening tool (Mini-Nutritional Assessment short-form (MNA-SF)). METHODS: 2252 veterans age 65 and older from 18 HBPC programs from across the country participated in the study. The study period was between April and September 2012. WinPepi (version 11.25) was used for descriptive analysis. RESULTS: We found that the prevalence of malnutrition was 15% (344/2252) and the prevalence of at risk for malnutrition was 40.3% (909/2252). DISCUSSION: The MNA-SF is an efficient nutrition screening tool and it can be successfully used for the elderly veterans. The prevalence of malnutrition among veterans was high compared to the community dwelling U.S. civilian elderly population. By preventing and treating malnutrition, health care systems should be able to reduce overall health care costs.

Bortezomib-induced peripheral neurotoxicity in human multiple myeloma-bearing mice.

The proteasome inhibitor bortezomib is an antineoplastic drug mainly used for the treatment of multiple myeloma (MM). Despite its effectiveness, bortezomib clinical use is often limited by the onset of peripheral neuropathy (BiPN). To better understand the mechanisms of BiPN several rat and mice models have been proposed, but no studies in MM-bearing animals allowing to test the antitumor activity of the selected schedules and the role of MM by itself in peripheral nervous system damage have been reported to date. Here, we carried out a study using immunodeficient C.B-17/Prkdcscid (SCID) mice injected with RPMI8266 human MM cells and treated with bortezomib 1 mg/kg once a week for five weeks. Animals were assessed with neurophysiological, behavioral and pathological methods and tumor volume measurement was performed along the study. At the end of the study BiPN was evident in bortezomib-treated animals, and this neurotoxic effect was evident using a schedule able to effectively prevent tumor growth. However, neurophysiological and pathological evidence of MM induced peripheral nervous system damage was also reported. This model based on MM-bearing animals is more reliable in the reproduction of the clinical setting and it is, therefore, more suitable than the previously reported models of BiPN to study its pathogenesis. Moreover, it represents an optimal model to test the efficacy of neuroprotective agents and at the same time their non-interference with bortezomib antineoplastic activity.

Inhibition of Candida albicans adhesion on medical-grade silicone by a Lactobacillus-derived biosurfactant.

AIMS: The study aimed at investigating the ability of biosurfactant (BS) produced by a Lactobacillus brevis isolate (CV8LAC) to inhibit adhesion and biofilm formation of Candida albicans on medical-grade silicone elastomeric disks (SEDs). METHODS AND RESULTS: Biosurfactant activity was evaluated at physiological conditions, by means of co-incubation and precoating assays. Additionally, BS extract was tested for antifungal susceptibility against C. albicans in both planktonic and sessile form. Biofilm covered surface and hyphae and blastospores occurrence were quantified by scanning electron microscopy (SEM) and image analysis. BS did not inhibit growth of C. albicans in both planktonic and sessile form. Nevertheless, co-incubation with 2000 µg ml(-1) BS significantly reduced biofilm formation on SEDs surface by 89, 90 and 90% after 24, 48 and 72 h of incubation. Fungal adhesion and biofilm formation to precoated SEDs was reduced by 62, 53, 50 and 44% after 1.5, 24, 48 and 72 h. SEM showed a significant reduction of biofilm covered surface in precoated disks but no differences in the production of hyphae or blastospores, except at 1.5 h of incubation. CONCLUSIONS: This study demonstrated that CV8LAC BS has the ability to counteract significantly the initial deposition of C. albicans to silicone surfaces and to effectively slow biofilm growth. SIGNIFICANCE AND IMPACT OF THE STUDY: The anti-adhesive properties of the CV8LAC BS suggest a potential role of the coating for preventing fungal infection associated to silicone medical devices.

The combined therapeutical effect of metal-based drugs and radiation therapy: the present status of research.

Conventional chemotherapy and radiation treatment are two cornerstones of cancer treatment but efforts are required to improve their "therapeutic window". The development of metal complexes, including platinum, has had an enormous impact on current cancer chemotherapy. However, these chemotherapeutic drugs can be employed only in the management of a limited number of cancers and, furthermore, their use causes significant side effects. Research over the past 10 years has produced new complexes containing heavy atoms other than platinum, such as iron, cobalt, or gold, which have been used in phase I and phase II trials. Recent preclinical research has shown promising results also using titanium, ruthenium, copper and silver. The anticancer activity of metal-based compounds and nanoparticles (gold and gadolinium in particular) is presently under evaluation in several laboratories in combination with or without X-ray therapy. In fact, if present in sufficiently high concentrations in the tumors, metals can act as a radiotherapy adjuvant: they possess an increased capability to absorb the X-ray radiation with respect to the water-based tissues. Low energy electrons will be then released close to the metal and, therefore, determine a local dose enhancement. This review will focus on the anticancer properties of new drugs and on the rationale for testing their usefulness in combined treatment.

Outcomes of renal transplantation in patients with major lower limb amputation.

INTRODUCTION: The impact of severe peripheral vascular disease on graft survival in patients undergoing renal transplantation is poorly defined. The aim of our study is to establish outcomes in renal transplant recipients who have severe peripheral vascular disease necessitating major lower limb amputation. METHODS: Data for patients undergoing renal transplantation from January 2001-December 2010 was extracted from a regional transplantation database. Patients undergoing lower limb amputation pre- and post-transplantation were identified and outcome measures including delayed graft function, biopsy-proven acute rejection, serum creatinine level at 1 year, and graft loss and recipient survival at 1 year and long-term were compared with patients who did not undergo amputation. Student t and Pearson's chi-squared tests were used to compare patients with and without amputation and Kaplan-Meier curves were used for survival analysis. A P value < .05 is considered statistically significant. RESULTS: A total of 762 patients underwent renal transplantation. Four (0.5%) patients had an amputation before transplantation and 16 (2.1%) underwent amputation after transplantation. Serum creatinine levels at 1 year were significantly higher in patients who had amputation after transplantation (308.5 ± 60.8 µmol/l vs 177.6 ± 6.4 µmol/l; P = .03). During longer follow-up (mean: 2053.1 ± 58.3 days), patients who underwent amputation after transplantation had a higher rate of graft loss (P < .01) and higher death rate (P < .01). CONCLUSION: The requirement for amputation after renal transplantation is associated with poor long-term graft and patient survival and higher serum creatinine levels at 1 year. Patients at increased risk of severe peripheral vascular disease should be identified and measures taken to reduce the long-term risk.

The impact of socioeconomic deprivation on outcomes following renal transplantation in the West of Scotland.

BACKGROUND: Social deprivation is associated with increased mortality for patients on renal replacement therapy. Patients from lower socioeconomic categories have reduced access to transplantation. However, the impact of social deprivation on outcomes following renal transplantation is unknown. METHODOLOGY: We undertook a retrospective analysis of all patients undergoing renal transplantation at a single center serving the West of Scotland over the 10-year period 2000 to 2010 (n = 705). Postcode data permitted calculation of a Scottish Index of Multiple Deprivation (SIMD) score, which was analyzed in quartiles from 0% to 25% (least deprived) to 75% to 100% (most deprived). Outcomes measures were graft loss, mortality, creatinine at 1 year, delayed graft function (DGF), and biopsy-proven acute rejection (BPAR). Kaplan-Meier survival analysis was undertaken (P < .05 is significant). Results are presented as percentages of the total population in SIMD quartiles 0% to 25%, 25% to 50%, 50% to 70%, and 75% to 100%, respectively. RESULTS: Mean follow-up was 5.86 ± 0.11 years. There was no difference in survival following renal transplantation depending on SIMD (89.6%, 87%, 88.4%, 90.2%; P = .82). There was improved graft survival in the least socioeconomically deprived; however, this was not significant (80%, 69.9%, 74.1%, 73.8%; P = .34). Similarly, there was a nonsignificant trend toward lower creatinine at 1 year in the least deprived patients (163.5 ± 12.8, 211.7 ± 19.5, 170.2 ± 9.8, 197.1 ± 6.9; P = .07). There was no difference in rates of DGF (P = .47), primary nonfunction (P = .17), or BPAR (P = .97) depending on socioeconomic status. The proportion of patients undergoing living donor transplantation was similar across the range of SIMD (23.9%, 27.6%, 25.5%, 21.8%; P = .76). CONCLUSIONS: Social deprivation does not affect either graft or patient survival after renal transplantation. Additionally, it did not influence the rate of living donor renal transplantation in our patient population.

A single center experience of abdominal wall graft rejection after combined intestinal and abdominal wall transplantation.

We report our outcomes following combined intestinal and abdominal wall transplantation, focusing on the presentation and treatment of acute rejection of the abdominal wall vascularized composite allograft (VCA). Retrospective analysis of all patients with combined intestinal/VCA transplantation was undertaken. Graft abnormalities were documented photographically and biopsies taken, with histological classification of rejection according to Banff 2007 guidelines. We have performed five combined intestinal and abdominal wall transplants to date. Two patients developed erythematous, maculopapular to papular eruptions confined to the VCA, histologically confirmed as grade II/III rejection, yet with normal bowel on endoscopy. Both patients' rashes resolved within 72 h of increasing immunosuppressive treatment. One patient later developed a recurrence of the rash, confirmed as skin rejection, but did not immediately seek medical attention. Treatment was therefore delayed, and mild intestinal rejection developed. We describe the rash associated with VCA rejection, and propose that while the skin of an abdominal wall VCA may reject independently of the intestinal allograft, delay in treatment of rejection episodes may result in rejection of the intestinal graft.

The effect of Photon Activation Therapy on cisplatin pre-treated human tumour cell lines: comparison with conventional X-ray irradiation.

Cisplatin is an antineoplastic drug widely used for the treatment of several solid tumours. However, the side effects related to cisplatin-based anticancer therapy often outweigh the benefits. Therefore, the identification of new anticancer strategies able to offer a better toxicity profile while maintaining the same level of efficacy as platinum-based treatments would be highly desirable. We assessed the efficacy of synchrotron radiation in triggering the Auger effect in human A549 non-small cell lung cancer and IGROV-1 ovarian cancer cells pre-treated with cisplatin. Cisplatin was chosen as the carrier of platinum atoms in the cells because of its alkylating-like activity and the irradiation was done with monochromatic beams above and below the platinum K-shell edge (78.39 keV). On cisplatin-treated cells, at concentrations allowing 80 percent of cell survival with respect to controls, no differences were observed in cell viability when they were irradiated either above or below the K-shell edge of platinum, suggesting that cisplatin toxicity can mask the enhancement of cell death induced by the irradiation. At lower cisplatin concentrations allowing 95-90 percent of cell survival, an enhancement in cellular death with respect to conventional irradiation conditions was clearly observed in all cancer types when cells were irradiated with beams either above or below the platinum K-shell edge. Our results lend additional support to the suggestion that the Photon Activation Therapy in combination with cisplatin treatment should be further explored in relevant in vivo models of glioma and non-glioma cancer models.

Functionalized mesoporous silica nanoparticles: a possible strategy to target cancer cells reducing peripheral nervous system uptake.

Mesoporous silica materials (MSM) have been proposed as promising tools for cell specific drug delivery or fluorescent cell tracking. In cancer therapy there is an urgent need to develop a cancer cell specific drug carrier able to limit the non-specific uptake of the drug by normal cells thereby reducing serious side effects. Chemotherapy induced peripheral neurotoxicity (CIPN) is one of the most clinically relevant side effects linked to the use of several antineoplastic drugs. In this study we showed that the uptake of MSM (synthesized using a PEG surfactant-based interfacial synthesis procedure), functionalised with folic acid (MSM-FOL) after 1, 6 and 24 hours is very limited in neuronal-like cellular systems such as differentiated SH-SY5Y human neuroblastoma cells and rat embryonic dorsal root ganglia sensory neurons. By contrast, the nanoparticles are highly internalized in A549 and IGROV-1 cancer cells. The 6 hour-treatment of A549 and IGROV-1 cells with nanoparticles loaded with the antineoplastic drug cisplatin (CP) induced significant cytotoxicity with respect to CP alone. These results were observed treating IGROV-1 cells with 25 and 50 µg/ml nanoparticles doses (corresponding respectively to CP 6.25 and 12.5 µM) and treating A549 with 50 µg/ml.Our results demonstrated a selective uptake of functionalized MSM suggesting them as promising tools for targeted antineoplastic therapy. Further studies will be necessary in order to confirm if this approach may be useful in reducing neurotocity of anticancer drugs.

CCR3 induced-p42/44 MAPK activation protects against staurosporine induced-DNA fragmentation but not apoptosis in airway smooth muscle cells.

BACKGROUND: Chemokine receptors (CCRs) are expressed on airway smooth muscle (ASM) cells. As their ligands are present in the airways in asthma, we hypothesized that ASM CCR activation could promote the increase in ASM mass seen in patients with chronic asthma. OBJECTIVE: To determine which CCRs are expressed by ASM cells and their potential functional relevance to the chronic airway changes seen in asthma. METHODS: CCR expression in primary ASM cell cultures and airway biopsies from patients with and without asthma was examined by RT-PCR, fluorescence-activated cell sorting and immunohistochemistry. ASM p42/44 MAPK activity, proliferation, migration and apoptosis were examined by western blotting, thymidine incorporation, transwell assay and TUNEL assay respectively. RESULTS: CCR3 was the most frequently expressed CCR protein and was present on 79 ± 14% of cells. CX3CR1 and CXCR6 were present on 6% and 11% of cells respectively. CCR3 ligands CCL11 and CCL24 caused rapid activation of p42/44 MAPK but not Akt. CCR3 activation did not affect ASM proliferation, migration or VEGF secretion. DNA fragmentation detected by TUNEL staining could be induced by staurosporine and Fas activation although only Fas activation resulted in caspase 3 cleavage. CCL11 and CCL24 protected ASM cells against DNA fragmentation dependent upon p42/44 MAPK activity only via caspase 3 independent pathways. CCR3 was expressed in the smooth muscle and epithelium in the airways of patients with and without asthma. Smooth muscle cell DNA fragmentation in the airways of patients with stable asthma and controls was very uncommon. CONCLUSIONS AND CLINICAL RELEVANCE: CCR3 is strongly expressed by ASM cells in vitro and in vivo. Protection against cell death by CCR3 activation is dependent on p42/44 MAPK but does not affect caspase 3 mediated apoptosis.

The role of glutamate in diabetic and in chemotherapy induced peripheral neuropathies and its regulation by glutamate carboxypeptidase II.

Glutamate has been implicated in the pathogenesis of several diseases on the central nervous system, but recent studies have also suggested that it can be involved also in the onset and course of peripheral neuropathies. Given the increasing evidence of this possibility, several attempts have been performed in order to modulate its activity. Among them, glutamate carboxypeptidase II (GCP II) inhibition demonstrated promising results in different models of peripheral nerve damage, including diabetic and toxic neuropathies.

Drug transporters in chemotherapy induced peripheral neurotoxicity: current knowledge and clinical implications.

Several antineoplastic drugs induce severe and dose-limiting peripheral neurotoxicity that can significantly affect the quality of life of cancer patients and cause chronic discomfort. Despite extensive investigation, the fine mechanisms of this side-effect remain unclear. It has recently been suggested that several classes of drug transporters are involved in the genesis of chemotherapy induced peripheral neurotoxicity. Furthermore, the differential distribution and activity of these transporters could also explain the higher sensitivity of the peripheral rather than central nervous system tissues to the toxic action of the anticancer agents. These observations may have important therapeutic implications. In fact, the characterization of the proteins that mediate significant transport of clinically relevant drugs in the nervous system, and the understanding of their changes in the different pathological conditions are important in order to elucidate pathogenetic mechanisms and to identify new potential therapeutic targets so as to limit the severity of chemotherapy-induced peripheral neurotoxicity. This review will be focused on the most recent research progress on the role of drug transporters in chemotherapy-induced peripheral neurotoxicity, and we will discuss the possibility of targeting these transporters as a new and interesting potential strategy for the treatment of the neurotoxic side-effects of antineoplastic drugs.

Third cranial nerve palsy? Look for a sicca syndrome.

Sjogren's syndrome (SS) is a systemic autoimmune disorder, and neurological involvement may frequently occur. Here we describe a 79-year-old woman who came to our attention for a sudden right incomplete 3rd cranial nerve palsy. Following extensive investigations, a diagnosis of primary SS was reached, and the patient recovered after treatment with ev Ig and steroids. Therefore, we suggest that SS should be considered in apparently idiopathic 3rd cranial nerve palsies, since, with the appropriate treatment, they might be transient and reversible.

Unequal access and unmet need: neurotic disorders and the use of primary care services.

In this paper we use data from the National Survey of Psychiatric Morbidity to examine how many people with neurotic disorders receive professional evaluation, and how this is affected by clinical and sociodemographic differences. We hypothesized that psychiatric symptoms and attendant dysfunctions would both have an effect on contacting, and that key demographic variables would not. The household component of the British National Surveys of Psychiatric Morbidity was based on a random sample of >10,000 subjects. Lay interviewers using the CIS-R established psychiatric symptoms and ICD-10 diagnosis. Social dysfunction was tapped by asking about difficulties in performing seven types of everyday activity. We examined symptom score, ADL deficit score, and demographic variables in relation to contact with primary care physicians for psychiatric symptoms. The major determinant of contacting a primary care physician was severity, mainly due to the level of psychiatric symptoms, but with an independent contribution from social dysfunction. There were also significant contributions from sex, marital status, age, employment status, and whether the subject had a physical condition as well. The major influence on whether people seek the help of their family doctors for mental health problems is the severity of disorder. Although there are some social inequalities in access to family doctors, these are less important. The most salient finding from our study is that even people suffering from high levels of psychiatric symptoms very often do not have contact with professionals who might help them.

Neurotic disorders and the receipt of psychiatric treatment.

Access to psychiatric treatment by people with neurotic disorders in the general population is likely to be affected both by the severity of disorder and by sociodemographic differences. In the household component of the National Surveys of Psychiatric Morbidity >10,000 subjects in Great Britain with psychiatric symptoms were interviewed using the CIS-R. They were also asked about difficulties experienced in performing seven types of everyday activity. All subjects classed as having an ICD-10 disorder were questioned about their experience of treatment with antidepressants, hypnotics, and counselling or psychotherapy. Less than 14% of people with current neurotic disorders were receiving treatment for them. Within the previous year, only a third had made contact with their primary care physician for their mental problem: of these <30% were receiving treatment. Overall, 9% of people with disorders were given medication and 8% counselling or psychotherapy. A diagnosis of depressive episode was that most associated with antidepressant medication. Treatment access was affected by employment status, marital status, and age, but the major determinant was symptom severity. Neither sex nor social class influenced which people received treatment. People with psychiatric disorders seldom receive treatment, even when they have consulted their primary care physician about them. In many cases, this must represent unmet needs with a strong claim on health resources. There are also inequalities in the receipt of treatment, although the major influence is the severity of disorder.

Unequal access and unmet need: neurotic disorders and the use of primary care services.

BACKGROUND: In this paper we use data from the National Survey of Psychiatric Morbidity to examine how many people with neurotic disorders receive professional evaluation, and how this is affected by clinical and sociodemographic differences. We hypothesized that psychiatric symptoms and attendant dysfunctions would both have an effect on contacting, and that key demographic variables would not. METHOD: The household component of the British National Surveys of Psychiatric Morbidity was based on a random sample of > 10,000 subjects. Psychiatric symptoms and ICD-10 diagnosis were established by lay interviewers using the CIS-R. Social dysfunction was tapped by asking about difficulties in performing seven types of everyday activity. We examined symptom score, ADL deficit score and demographic variables in relation to contact with primary care physicians for psychiatric symptoms. RESULTS: The major determinant of contacting a primary care physician was severity, mainly due to the level of psychiatric symptoms, but with an independent contribution from social dysfunction. There were also significant contributions from sex, marital status, age, employment status and whether the subject had a physical condition as well. CONCLUSIONS: The major influence on whether people seek the help of their family doctors for mental health problems is the severity of disorder. Although there are some social inequalities in access to family doctors, these are less important. The most salient finding from our study is that even people suffering from high levels of psychiatric symptoms very often do not have contact with professionals who might help them.