Effects of antiretroviral therapy on proprotein convertase subtilisin/kexin 9: focus on lipids, inflammation and immunovirological parameters.

OBJECTIVES: Plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol metabolism, have been reported to have an increasing trend in people living with HIV (PLWH) compared with controls. We assessed the impact of different antiretroviral (ARV) regimens on plasma PCSK9 levels as well as plasma lipids, systemic inflammation and immunovirological parameters. METHODS: Eighty HIV-positive ARV therapy (ART)-naïve PLWH and 40 uninfected controls were retrospectively enrolled. At baseline and 3, 6 and 12 months after ART initiation, plasma PCSK9 levels, lipids, high-sensitivity C-reactive protein (hs-CRP), HIV-1 RNA levels and CD4 T-cell count were measured. RESULTS: Baseline PCSK9 levels were significantly more elevated in PLWH and were associated with HIV-1 RNA levels (P < 0.001), CD4 T-cell counts (P < 0.001), triglycerides (P < 0.001) and high-density lipoprotein (HDL) cholesterol (P < 0.001), but not with total cholesterol, low-density lipoprotein (LDL) cholesterol and lipoprotein(a) levels. The prescription of ART was paralleled by significant decreases in plasma PCSK9 and hs-CRP levels, and increases in total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and lipoprotein(a), independent of regimen. CONCLUSIONS: PCSK9 levels, along with systemic inflammation, were progressively reduced following the initiation of an effective ART. However, at the end of the study PCSK9 levels remained higher than in controls and did not correlate with any of the lipid variables.

Daily bathing with 4% chlorhexidine gluconate in intensive care settings: a randomized controlled trial.

OBJECTIVES: To investigate whether daily bathing with a soap-like solution of 4% chlorhexidine (CHG) followed by water rinsing (CHGwr) would decrease the incidence of hospital-acquired infections (HAI) in intensive care settings. METHODS: Randomized, controlled trial; infectious diseases specialists were blinded to the intervention status. All patients admitted to the Intensive Care Unit (ICU) and to the Post-operative Cardiosurgical Intensive Care Unit (PC-ICU) of the University Hospital of Perugia were enrolled and randomized to the intervention arm (daily bathing with 4% CHGwr) or to the control arm (daily bathing with standard soap). The incidence rate of acquisition of HAI was compared between the two arms as primary outcome. We also evaluated the incidence of bloodstream infections (BSI), central-line-associated BSI (CLABSI), ventilator-associated pneumonia (VAP) and catheter-associated urinary tract infections (CAUTI), and 4% CHGwr safety. RESULTS: In all, 449 individuals were enrolled, 226 in treatment arm and 223 in control arm. Thirty-four individuals of the 226 (15%) and 57 (25.6%) suffered from at least an HAI in the intervention and control arms, respectively (p 0.008); 23.2 and 40.9 infections/1000 patient-days were detected in the intervention arm and control arm, respectively (p 0.037). The incidence of all bloodstream infections (BSI plus CABSI) was significantly reduced in the intervention arm (9.2 versus 22.6 infections/1000 patient-days, p 0.027); no differences were observed in the mortality between the two arms. CONCLUSIONS: Daily bathing with 4% CHGwr significantly reduced HAI incidence in intensive care settings. CLINICALTRIAL. GOV REGISTRATION: NCT03639363.

Five year experience of the treatment of squamous cell carcinoma of the anus.

OBJECTIVES: The best treatment of early stage anal squamous cell carcinoma (SCC) is under debated. Wide local excision (WLE) may be considered adequate for stage 1 anal margin cancer. This study demonstrates our experience in treatment of patients with SCC over 5 years. PATIENTS AND METHODS: We conducted a retrospective study of patients who had undergone anal screening or anal cancer surveillance between October 2010 and 2015 in our department. Each patient underwent anal Pap test, HPV test PCR HPV DNA and cytology by Thin Prep. The examinations were performed by Proctostation THD©. Data were collected and analysed. RESULTS: We included 25 patients, 16 male (64%) and 9 female (36%). Twenty-four patients had SCC and 1 patient had adenocarcinoma. Of this cohort: 10 underwent chemoradiotherapy (CRT) because T3-4 N1-2 M0, 13 underwent only surgery because T1/T2 and 2 patients had CRT and surgery because they already have had anal cancer treated in the past with CRT. Seventeen patients (68%) of this cohort, including 5 with micro-invasive SCCs, had regular follow-up without recurrences. Four patients (17%) died from metastatic disease and 4 patients (17%) had recurrent disease. CONCLUSIONS: In this small cohort we demonstrated satisfactory results in treatment of SCCs, underlining the effective role of surgery in early stages of SCC. Screening program and follow up were fundamental to identify early stage and recurrent disease. Also we found the High-resolution video-proctoscopy a valid diagnostic tool.

FXR activation improves myocardial fatty acid metabolism in a rodent model of obesity-driven cardiotoxicity.

BACKGROUND AND AIMS: Obesity-driven lipotoxicity is a risk factors for cardiovascular disease. The Farnesoid X Receptor (FXR) is a bile acids sensor and member of the nuclear receptor superfamily. Activation of FXR lowers plasma triacylglycerols and glucose levels through a mechanism that involves both the repression of key regulatory genes in the liver and the modulation of insulin sensitivity in peripheral tissues. In the present study we have investigated whether administering obese (fa/fa) Zucker rats, a genetic model of obesity associated with dyslipidemia and insulin resistance, with an FXR ligand protects against lipid-induced cardiomyopathy. METHODS AND RESULTS: FXR is expressed in neonatal cardiomyocytes and the treatment with FXR agonists, chenodeoxycholic acid (CDCA), and GW4064, increased the mRNA expression of FXR and its canonical target gene, the small heterodimer partner (SHP), as well as proliferator-activated receptor alpha PPARα, acyl-CoA oxidase (AOX) and pyruvate dehydrogenase kinase (PDK-4). Feeding obese fa/fa rats with CDCA, 12 weeks, reduced hyperinsulinemia and hyperlipidaemia. The histological-pathological analysis of hearts demonstrated that treatment with the FXR ligand reduced lipid heart content decreased the rate of apoptosis, fibrosis scores and restored heart insulin signalling. Chronic CDCA administration, in the heart, induced PPARα and PPARα-regulated genes involved in ß-oxidation. CONCLUSION: FXR agonism exerts beneficial effects in a genetic model of lipid-induced cardiomyopathy. The striking benefit of this therapy on cardiac function in this model warrants an effort to determine whether a counterpart of this activity translates in human settings.

Trends and challenges in tuberculosis in a medium-sized southern European setting.

Trends in tuberculosis (TB) admissions over 40 years at the Infectious Diseases Clinic of Perugia University Hospital, Perugia, Italy, show that in the last decade non-Italian TB case admissions outweighed those of Italians, with a large number of cases from Eastern Europe (25.2%) and Africa (23.4%). Non-Italians tended to be younger and were generally new pulmonary TB cases, and drug resistance was also more common. Overall, the number of multidrug-resistant cases increased. Only one case occurred in a native-born Italian, and five of seven cases had newly diagnosed TB. In low TB incidence settings such as Perugia, Italy, TB prevention and control programmes for the foreign-born need to be reinforced.

Endothelial and platelet function alterations in HIV-infected patients.

The HIV epidemic has huge dimensions: in 2009, 33.3million people worldwide, including 2.5million children, were affected by human immunodeficiency virus (HIV) infection. The introduction of Highly Active Anti-Retroviral Therapy (HAART) has significantly modified the course of HIV disease, with longer survival and improved quality of life, but it has simultaneously lead to the appearance of previously unrecognized complications, such as ischemic cardiovascular events. Many studies have shown a higher rate of premature atherosclerosis in patients with HIV infection, leading to coronary, cerebrovascular, or peripheral arterial disease. However, it is still debated whether cardiovascular complications are a consequence of HIV infection itself or of the long-term use of HAART. In particular, myocardial infarction has been suggested to be associated with the use of abacavir. Endothelial dysfunction and platelet activation are markers of atherosclerosis and of increased cardiovascular risk. Here we review the evidence that endothelial dysfunction and platelet alterations are associated with chronic HIV infection, the possible role of different HAARTs, and the possible pathophysiologic mechanisms. Potential therapeutic implications are also discussed.

Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA.

6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liver-related metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a reduction a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre-clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.

Malignant syphilis with ocular involvement in an HIV-infected patient.

Malignant syphilis is now considered a rare disease, more commonly affecting individuals with poor health, malnutrition or HIV infection. We present a 34-year-old man with HIV infection who developed multiple atypical cutaneous ulcerations, leonine facies, a scleral nodule and keratitis with visual loss. The diagnosis of malignant syphilis was delayed due to the insidious presentation, but was confirmed via immunohistochemical (IHC) staining with anti-Treponema antibodies of a skin biopsy. Significant clinical improvement was observed following a 15-day course of penicillin and tigecycline therapy. In advanced HIV disease, cutaneous manifestations are often difficult to identify and present a challenge for the clinician. Clinical manifestations of secondary syphilis vary greatly, earning the epigram of 'the great imitator'. It is important to recognize atypical presentations of syphilis, especially among HIV-infected individuals. Unlike historical cases of malignant syphilis, Treponema pallidum was found in the tissue section using IHC staining methods. We emphasize the importance of lues maligna in the differential diagnosis of HIV-infected patients with diffuse ulceronodular lesions as well as the usefulness of histological investigations and IHC studies.

Counter-regulatory role of bile acid activated receptors in immunity and inflammation.

In addition to their role in dietary lipid absorption bile acids are signaling modules activating nuclear receptors and at least one G-protein coupled receptors named the TGR5. With a different rank of potency primary and secondary bile acids activates a subset of nuclear receptors including the farnesoid-X-receptor (FXR, NR1H4); the constitutive androstane receptor (CAR, NR1H3), the pregnane-x- receptor (PXR, NR1H2), the vitamin D receptor (VDR, NR1H1). Originally, these receptors were characterized for their role as bile acid and xenobiotic sensors, emerging evidence, however, indicates that FXR, PXR and VDR and their ligands are important for the modulation of immune and inflammatory reactions in entero-hepatic tissues. The immune phenotype FXR deficient mice indicates that these receptors are essential for the maintenance of immune homeostasis. A common theme of all bile acid-activated receptor is their ability to counter-regulate effector activities of cells of innate immunity establishing that signals generated by these receptors and their ligands function as a braking signals for inflammation in entero-hepatic tissues. In this review, we will spotlight the molecular mechanisms of receptor/ligand function and how bile acid-activated receptors regulate the innate immunity in the gastrointestinal tract and liver. The ability of these receptors to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in immune-mediated diseases.

Management of hepatitis B virus reactivation in patients with hematological malignancies treated with chemotherapy.

INTRODUCTION: Hepatitis B virus (HBV) reactivation is a major cause of morbidity and mortality in patients with hematological malignancies who receive cytotoxic chemotherapy. We have therefore carried out a prospective observational study out to assess the incidence, prevalence, and clinical course ina cohort of these patients. METHODS: HBV and HCV markers and liver function indices were monitored prospectively in 318 consecutive patients(171 males, 147 females; mean age 57 years) with hematological malignancies, who had been referred to the Hematology Division, Perugia University, between October 2005 and March 2007 and followed up for at least 6 months. RESULTS: At diagnosis, 32 patients (10%) had received HBV vaccination; 30 were responders. At least one HBV marker was positive in 70/318 patients (22%): 14 (20%) were HBsAg-positive(HBV surface antigen-positive), 13 (19%) were only anti-HBc positive (antibodies to HB core antigen), and 43(61%)were anti-HBc and anti-HBs positive. Twelve HBsAg+ patients received nucleoside/nucleotide analogs (adefovir [six patients],lamivudine [four], and combined adefovir/lamivudine[two non-responders to lamivudine]). After 6 months of therapy, HBV-DNA was negative and transaminases were normal in nine of these 12 patients (adefovir [six], lamivudina[two], adefovir + lamivudina [one]). Seroreversion was achieved in 3/13 patients (23%) who were only anti-HBc positive;all were on rituximab therapy and received adefovir. Seroreversion was not observed in any of the 43 patients who were anti-HBc- and anti-HBs positive. CONCLUSIONS: Essential to the management of patients with hematological malignancies undergoing chemotherapy are surveillance and prophylaxis of HBV infection together with prompt administration of nucleoside/nucleotide analogs in cases of reactivation and/or seroreversion.

Occult hepatitis B virus infection in a cohort of HIV-positive patients: correlation with hepatitis C virus coinfection, virological and immunological features.

BACKGROUND: An evaluation of the prevalence of occult hepatitis B virus (HBV) infection in HIV-positive individuals is important as HBV infection may have an impact on the outcome of the liver disease in these patients. MATERIALS AND METHODS: Of the 1,593 HIV-positive subjects enrolled in the Italian Cohort Naïve Antiretroviral (ICONA) program, 175 (10.9%) were selected for inclusion in the study on the basis of hepatitis B surface antigen (HBsAg) negativity and antibody to hepatitis B core antigen (anti- HBc) positivity; 101/175 (58%) were also anti-hepatitis C virus (HCV) positive. HBV-DNA was detected in plasma using a highly sensitive PCR assay (detection limit: 2.6 copies/ml). Two different genomic regions were assayed. Quantification was performed by real-time PCR. The HBV genotype was determined in 20 cases with occult HBV infection. Data on the antiretroviral therapy (ART) regimen was obtained in 169 individuals: 53 (31.4%) patients were ART-naive, 46 (27.2%) were under ART without lamivudine or tenofovir, and the remaining 70 (41.4%) were under ART including lamivudine or tenofovir. RESULTS: 27/175 (15%) patients had detectable HBV-DNA in their plasma: 21/101 (21%) were anti-HCV positive and 6/74 (8%) were anti-HCV negative. Genotype D was invariably found in the 20 cases analyzed. Occult HBV infection was significantly higher in HCV-coinfected subjects: adjusted OR 5.02, 95% CI 1.31-19.26, p = 0.02. The value was not associated with immune status, HIV load, or ART regimen. CONCLUSIONS: In relation to the high prevalence of occult HBV infection, particularly in HIV/HCV-coinfected individuals, it is necessary to clarify the clinical impact of this cryptic infection by monitoring HBV-DNA in plasma using the correct approach. Similarly to HBsAg-positive individuals of the Mediterranean area, HBV genotype D is invariably detected in this cohort of HIV-infected patients with occult HBV infection.

Peginterferon plus Ribavirin for chronic hepatitis C in opiate addicts on methadone/buprenorphine maintenance therapy.

BACKGROUND: In developed countries hepatitis C is prevalently transmitted by intravenous drug users (IDUs). The problems associated with management of HCV hepatitis in these patients have, in the past, discouraged treatment. AIM: To evaluate efficacy, safety and tolerability of a standard Peginterferon (Peg-IFN) alpha-2b or alpha-2a plus Ribavirin treatment in IDUs who were receiving methadone or buprenorphine. METHODS: A multi-centre prospective observational study performed from September 2003 to September 2006 in Central Italy (Umbria and Marches regions). A shared care model of HCV management was used which integrated a multidimensional, multidisciplinary approach. RESULTS: Sixty-five subjects were evaluated and 52 satisfied inclusion criteria. Forty-five completed treatment (25 with Peg-IFN alpha-2b, 20 with Peg-IFN alpha-2a), a total of 37 showed a biochemical/virological response at the end of treatment (ITT 71.1%), 26 had a sustained virological response (ITT 50%; 38.4% of cases genotype 1-4, 61.6% genotype 3-2). CONCLUSIONS: The results indicate that patients on maintenance treatment with methadone/buprenorphine can be treated for HCV. The success rate was fairly good; tolerability and side effects were similar to those reported in non-IDU patients. Close cooperation with specialists in drug addiction and psychiatrists is however essential for success.

Topical cidofovir for severe warts in a patient affected by AIDS and Hodgkin's lymphoma.

We describe a 42-year-old man with AIDS and Hodgkin's lymphoma whose severe and recalcitrant cutaneous warts resolved following treatment with local 1% cidofovir. Clinically significant improvements were observed in a two-week period of therapy. In advanced HIV disease complicated by additional haematological malignancy, cutaneous warts may be difficult to treat and present a challenge for the attending physicians. In similar clinical condition topical anti-human papillomavirus therapy may prove to be safe and curative.

Nosocomial post-traumatic Rhizomucor soft tissue and bone infection treated with liposomial amphotericin B: case report.

Mucornycosis is a rare fungal infection most commonly occuring in patients with severe immunocompromise, diabetes, uremia or trauma. Only a few cases of non axial skeletal bone osteomyelitis have been reported. We report a case of nosocomial cellulitis and osteomyelitis complicating a posttraumatic bacterial infection, successfully treated with liposomial amphotericin B and surgical debridement. Traumatized patients with extensive tissue loss, receiving broad-spectrum antibiotics, can develop impaired immune responses and are at risk for fungal infections.

Clinical efficacy and tolerability of caspofungin in a renal transplant patient with Aspergillus flavus lung infection: case report.

Organ transplant recipients are at increased risk for severe invasive aspergillosis, and amphotericin deoxycholate has been the standard treatment for many years. Currently, however, lipid formulations are preferred due to their few side effects. Also, a number of new antifungal drugs have been developed including new azoles and echinocandins. Caspofungin is the first of the echinocandin derivatives patented to treat patients with invasive aspergillosis who are refractory or intolerant to other therapies. A renal transplant patient on immunosuppressive treatment with chronic hepatitis B virus infection was admitted with fever, hemophthisis and lung consolidation, diagnosed to be probably caused by Aspergillus flavus. The patient developed cholestatic hepatitis most likely related to itraconazole. Clinical failure and in vitro itraconazole resistance of the isolate was also documented while the patient was receiving itraconazole at a reduced dosage. Caspofungin was administered once a day as ambulatory treatment and was well tolerated. Clinical improvement was observed after 6 weeks of treatment and no hepatic toxicity was documented. Caspofungin seems to be a potentially useful antifungal agent in renal transplant patients with invasive aspergillosis. Further evaluation of the efficacy of caspofungin is needed.

Treatment of post-traumatic hand Staphylococcus aureus osteomyelitis with oral linezolid.

The Authors report on the use of linezolid for the treatment of three patients with osteomyelitis. All three patients had post-traumatic multisensitive hand bone methicillin-susceptible Staphylococcus aureus osteomyelitis, which did not respond to antimicrobial regimens including drugs in vitro active against the isolated strains. Clinical cure and microbiologic eradication was obtained with oral linezolid in all three patients. Linezolid was well tolerated. Mild thrombocytopenia was observed in one patient at the end of the third week of treatment and it was promptly resolved after the discontinuation of linezolid. Linezolid minimum inhibitory concentrations (MICs) consisted of 2 mg/l for all three S. aureus isolates while the bactericidal activity in vitro was not present up to the linezolid concentration of 32 mg/l. In spite of a lack of in vitro bactericidal activity, linezolid was effective in curing the patients and eradicating the infection. Trough and peak plasma concentrations of linezolid were above the MICs of the isolates. These values ranged from 3.93 to 14.95 mg/l at trough and 5.03 to 25.91 mg/l at peak. The oral bioavailability, pharmacokinetic profile and antibacterial spectrum of linezolid make this oxazolidonone antimicrobial an attractive drug for the treatment of chronic osteomyelitis. Prolonged administration requires careful surveillance for side effects, until these complications are better understood.

Fatal haemolytic uraemic syndrome in an AIDS patient with disseminated adenovirus and cytomegalovirus co-infection.

We describe a fatal case of haemolytic uraemic syndrome in a young woman with AIDS, and disseminated adenovirus (ADV) and cytomegalovirus (CMV) co-infection. We hypothesize that ADV/CMV co-infection may have a causative role in this clinical picture.

Penetration of moxifloxacin into bone in patients undergoing total knee arthroplasty.

OBJECTIVES: To investigate plasma and bone moxifloxacin concentrations following oral administration of a single or double dose of the drug, in order to consider its potential role in the treatment of osteomyelitis. PATIENTS AND METHODS: Thirty consecutive patients undergoing total knee arthroplasty were recruited. Three groups, of ten patients each, were formed: group A received moxifloxacin 400 mg orally 2 h (range 1.5-2.5) preoperatively, group B received moxifloxacin 400 mg orally 4 h (range 3.5-4.5) preoperatively and group C received moxifloxacin 400 mg orally 14 h preoperatively, followed by a second dose 2 h (range 1.5-2.5) preoperatively. During surgery, at the time of bone removal, a blood sample and aliquots of cortical and cancellous bone were collected and moxifloxacin concentrations were measured by HPLC. RESULTS: Mean plasma, cancellous bone and cortical bone concentrations were, respectively: 3.45, 1.89 and 1.43 mg/L for group A; 3.73, 1.81 and 1.56 mg/L for group B; and 6.26, 2.97 and 2.54 mg/L for group C. CONCLUSIONS: These data show a good penetration of moxifloxacin into both cancellous and cortical bone, with concentrations, after double dosing, exceeding the MIC90 for most pathogens involved in osteomyelitis and the clinic susceptibility breakpoint for Mycobacterium tuberculosis.