The Agmatine-Containing Poly(Amidoamine) Polymer AGMA1 Binds Cell Surface Heparan Sulfates and Prevents Attachment of Mucosal Human Papillomaviruses

The agmatine-containing poly(amidoamine) polymer AGMA1 was recently shown to inhibit the infectivity of several viruses, including human papillomavirus 16 (HPV-16), that exploit cell surface heparan sulfate proteoglycans (HSPGs) as attachment receptors. The aim of this work was to assess the antiviral activity of AGMA1 and its spectrum of activity against a panel of low-risk and high-risk HPVs and to elucidate its mechanism of action. AGMA1 was found to be a potent inhibitor of mucosal HPV types (i.e., types 16, 31, 45, and 6) in pseudovirus-based neutralization assays. The 50% inhibitory concentration was between 0.34 μg/ml and 0.73 μg/ml, and no evidence of cytotoxicity was observed. AGMA1 interacted with immobilized heparin and with cellular heparan sulfates, exerting its antiviral action by preventing virus attachment to the cell surface. The findings from this study indicate that AGMA1 is a leading candidate compound for further development as an active ingredient of a topical microbicide against HPV and other sexually transmitted viral infections.     

Risk Factors and Comorbidities for Onychomycosis: Implications for Treatment with Topical Therapy

A number of comorbidities and risk factors complicate the successful management of onychomycosis. Underlying conditions and patient characteristics, such as tinea pedis, age, and obesity, contribute to risk, whereas comorbidities, such as diabetes and psoriasis, can increase susceptibility to the disease. There are limited data on treatment effectiveness in these patients. Here, the authors review post hoc analyses of efinaconazole topical solution, 10%, in mild-to-moderate onychomycosis and present new data in terms of age and obesity. The only post hoc analysis to report significant differences so far is gender, where female patients do much better; however, the reasons are unclear. The authors report significant differences in terms of efficacy in obese patients who do not respond as well as those with normal body mass index (P=0.05) and in patients who have their co-existing tinea pedis treated compared to those in whom co-existing tinea pedis was not treated (P=0.025). Although there is a trend to reduced efficacy in older patients and those with co-existing diabetes, differences were not significant. More research is needed in onychomycosis patients with these important risk factors and comorbidities to fully evaluate the treatment challengse and possible solutions.Onychomycosis is a common problem in dermatology practice that can result in significant morbidity.1,2 Successful treatment has been difficult because of slow growth of the nail; patient comorbidities, such as diabetes, peripheral vascular disease, and psoriasis; and reluctance of prescribers and patients to prescribe or take oral medications because of “perceived” toxicity issues.The disease can have a major impact on the individual and other family members.3-5 Dystrophic nails can cause embarrassment, affecting a patient’s self-esteem, and may have a greater impact on quality of life (QoL) than the severity of the disease itself.6 Thickened nails can also be painful, causing discomfort in walking and affecting other aspects of daily living.3A number of underlying conditions, such as tinea pedis, nail damage, and nail psoriasis can contribute to risk as well as characteristics such as age and obesity. Underlying comorbidities, such as diabetes,7,8 cancer,7,9 immunodeficiency,10 or peripheral arterial disease,11 can increase susceptibility to onychomycosis.7 An inherited genetic predisposition to infection has also been identified.12Clinical trials provide guidance on likely treatment outcomes in these patients at risk. However, some comorbid conditions (i.e., peripheral vascular disease) can be exclusion criteria, many trials were not set up to specifically study certain comorbidities, and the demographics and disposition of patients who visit dermatology and podiatry practices can be very different from those enrolled in clinical trials.Recently, a number of post hoc analyses have been published on the use of efinaconazole topical solution, 10%, in the treatment of mild-to-moderate onychomycosis. Where data exist, it is the authors’ intention to review the findings in terms of the implications for successful treatment outcomes. In addition, they present new data with efinaconazole in terms of age and obesity.Aging is the most common risk factor for onychomycosis, most likely due to poor peripheral circulation, longer exposure to pathogenic fungi, repeated nail trauma, suboptimal immune function, and slower nail growth.13 In addition, various medical conditions more common in the elderly increase the risk of comorbid onychomycosis. Surveys suggest that overall the incidence is much higher in adults than in children, afflicting 0.6 percent of children under the age of 18 years, approximately 10 to 20 percent of adults and 15 to 40 percent of elderly people.14-16 However, prevalence rates do not necessarily correlate with consultations. Not all of the patients we see with onychomycosis are elderly. This could be attributed to the fact that onychomycosis may be considered a cosmetic problem by the younger patients who are more conscious of their appearance coming forward for therapy. The increased incidence in the younger population could also be due to their exposure to occupation-related trauma predisposing them to onychomycosis or the more common use of occlusive footwear.     

Manganese superoxide dismutase activity and incidence of hepatocellular carcinoma in patients with Child-Pugh class A liver cirrhosis: a 7-year follow-up study.

AIMS: To evaluate possible modifications in the manganese superoxide dismutase (MnSOD) activity during neoplastic transformation of a cirrhotic liver and to find out whether its assessment may have predictive value to identify cirrhotic patients at a higher risk of hepatocellular carcinoma (HCC). METHODS: Seventy-one consecutive subjects with Child-Pugh class A liver cirrhosis were recruited. At the time of enrolment, HCC was diagnosed in 20 cirrhotic patients. The 51 cirrhotic patients without HCC were followed up for the occurrence of tumour by 6-monthly screening for 7 years. During follow-up, 16 patients developed HCC. Seventy healthy subjects formed the control group. MnSOD activity was assayed spectrophotometrically. RESULTS: Serum MnSOD activity was significantly lower in 70 healthy subjects compared with 51 cirrhotic patients and 20 cirrhotic patients with HCC. Cirrhotic patients who developed HCC during follow-up showed significantly higher values of MnSOD activity than HCC-free patients. The best cut-off of MnSOD activity was 0.40 U/ml. At this cut-off, chi2 analysis revealed that MnSOD activity was significantly different between the HCC-free cirrhotic patients and cirrhotic patients who developed HCC. CONCLUSION: The present findings suggest that during neoplastic transformation of cirrhotic liver, an increase in MnSOD activity may occur already during the precancerous phase, making this enzyme a probable malignancy-associated parameter.     

Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment

OBJECTIVE: Acromegaly is a syndrome with a high risk of impaired glucose tolerance (IGT) and diabetes mellitus (DM). Somatostatin analogues, which are used for medical treatment of acromegaly, may exert different hormonal effects on glucose homeostasis. Twenty-four active acromegalic patients were studied in order to determine the long-term effects of octreotide-LAR and SR-lanreotide on insulin sensitivity and carbohydrate metabolism. DESIGN: Prospective study. PATIENTS: We studied 24 patients with active acromegaly, 11 males and 13 females, aged 50.7 +/- 12.7 years, body mass index (BMI) 30.1 +/- 4.8 (kg/m2). MEASUREMENTS: All patients underwent an oral glucose tolerance test (OGTT) and 12 also had an euglycaemic hyperinsulinaemic clamp. All patients were evaluated at baseline and after 6 months of somatostatin analogues therapy. RESULTS: Acromegalic patients showed low M-values in respect to the control group at baseline (P<0.05), followed by a significant improvement after 6 months of therapy (P<0.005 vs. baseline). Serum glucose levels at 120 min during OGTT worsened (P<0.05) during somatostatin analogs therapy in patients with normal glucose tolerance, but not in those with impaired glucose tolerance or diabetes mellitus. This was associated with a reduced (P<0.05) and 30 min delayed insulin secretion during OGTT. Also, HbA1c significantly deteriorated in all subjects after treatment (4.7 +/- 0.6% and 5.1 +/- 0.5%, basal and after six months, respectively, P<0.005). CONCLUSION: In acromegalic patients, somatostatin analogues treatment reduces insulin resistance, and also impairs insulin secretion. This may suggest that the use of oral secretagogue hypoglycaemic agents and/or insulin therapy should be considered rather than insulin sensitizers, as the treatment of choice in acromegalic patients who develop frank hyperglycaemia during somatostatin analogues therapy.     

Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines.     

Accurate estimate of pancreatic T2* values: how to deal with fat infiltration

Purpose

We examined different approaches aimed to deal with the signal fluctuation of pancreatic T2* values due to fat infiltration in order to obtain accurate estimates of iron overload.

Methods

Pancreatic T2* values were assessed in 20 patients (13 females, 37.24 ± 9.12 years) enrolled in the Myocardial Iron Overload in Thalassemia network without and with the application of fat suppression-FS (T2*-NoFS and T2*-FS). T2* values were assessed in three different ways: (1) from the immediate fit (original T2*); (2) discarding the echoes until the achievement of a good visual concordance between the signal and the model (final_vis T2*); (3) eliminating the echoes until the achievement of a fitting error (known) <5% (final_thres T2*).

Results

For the T2*-NoFS sequence the original T2* values were significantly higher than the final_vis T2* values (difference:4.8 ± 6.1 ms; P < 0.0001) and the final_thres T2* values (difference:4.3 ± 6.1 ms; P = 0.006). For the T2*-FS sequence the original T2* values were comparable to final_vis and final_thres T2* values. The original T2*-FS values were significantly different from the original T2*-NoFS values. The final_vis T2*-FS values were comparable to the final_vis T2*-NoFS values and the final_thresh T2*-FS values were comparable to the final_thresh T2*-NoFS values. For both T2*-FS and T2*-NoFS sequences, the final_thres T2* values were not significantly different from the final_vis T2* values and no bias was present.

Conclusions

In the clinical practice, an accurate pancreatic iron overload assessment should be done by applying FS and, when needed, by discarding the TEs until the fitting error goes below 5%.

     

IsdC from Staphylococcus lugdunensis Induces Biofilm Formation under Low-Iron Growth Conditions

Staphylococcus lugdunensis is a coagulase-negative staphylococcus that is a commensal of humans and an opportunistic pathogen. It can cause a spectrum of infections, including those that are associated with the ability to form biofilm, such as occurs with endocarditis or indwelling medical devices. The genome sequences of two strains revealed the presence of orthologues of the ica genes that are responsible for synthesis of poly-N-acetylglucosamine (PNAG) that is commonly associated with biofilm in other staphylococci. However, we discovered that biofilm formed by a panel of S. lugdunensis isolates growing in iron-restricted medium was susceptible to degradation by proteases and not by metaperiodate, suggesting that the biofilm matrix comprised proteins and not PNAG. When the iron concentration was raised to 1 mM biofilm formation by all strains tested was greatly reduced. A mutant of strain N920143 lacking the entire locus that encodes iron-regulated surface determinant (Isd) proteins was defective in biofilm formation under iron-limited conditions. An IsdC-null mutant was defective, whereas IsdK, IsdJ, and IsdB mutants formed biofilm to the same level as the parental strain. Expression of IsdC was required both for the primary attachment to unconditioned polystyrene and for the accumulation phase of biofilm involving cell-cell interactions. Purified recombinant IsdC protein formed dimers in solution and Lactococcus lactis cells expressing only IsdC adhered to immobilized recombinant IsdC but not to IsdJ, IsdK, or IsdB. This is consistent with a specific homophilic interaction between IsdC molecules on neighboring cells contributing to accumulation of S. lugdunensis biofilm in vivo.