IL-1 ß gene (+3954 C/T, exon 5, rs1143634) and NOS2 (exon 22) polymorphisms associate with early aseptic loosening of arthroplasties.

Aseptic prosthetic loosening (APL) and prosthetic joint infections (PJI) are frequent complications of hip and knee implants. Polymorphisms of cytokines and nitric oxide (NO), key inflammatory molecules in APL and PJI pathogenesis, could explain individual susceptibility to these complications. Three cytokines (IL-1-a, IL-1-ß, TNF-α) and two nitric oxide synthase (NOS2, NOS3) genes polymorphisms were genotyped in 77 APL and 117 PJI patients and 145 controls with aseptic hip or knee implants that were implanted for > 16 years. Plasma cytokines and nitrate-nitrite (NOx) levels also were measured. The TT genotype and T allele of (+3954 C/T, exon 5, rs1143634) IL-1ß polymorphism were more frequent in APL patients compared to controls (P = 0.03 and P = 0.02, respectively). No genotypic associations in PJI patients were observed. Plasma IL-6, TNF-α and NOx were significantly different between APL and controls (P < 0.0001). Plasma IL-1ß and IL-6 were significantly higher in APL T allele carriers vs. non-carriers (P < 0.03). Knee implant (HR 2.488, 95% CI 1.307-4.739, P = 0.005), male gender (HR 2.252, 95% CI 1.121-4.525, P = 0.023), carriages of the TT genotype of the (+3954 C/T) IL-1ß polymorphism (HR 3.704, 95% CI 1.274-10.753, P = 0.016) and AA genotype of the (exon 22) NOS2 polymorphism (HR 3.509, 95% CI 1.266-9.709, P = 0.016) were independently associated with a shorter implant survival by Cox regression. No genotypic associations in PJI patients were observed. Genotyping of IL-1ß (+3954 C/T, exon 5, rs1143634) and NOS2 (exon 22) polymorphisms could be useful as predictors of early hip or knee APL.

High-Level Carbapenem Resistance among OXA-48-Producing Klebsiellapneumoniae with Functional OmpK36 Alterations: Maintenance of Ceftazidime/Avibactam Susceptibility.

The aim of this work was to analyze outer membrane porin-encoding genes (ompK35 and ompK36) in a collection of OXA-48 producing Klebsiella pneumoniae, to assess the effect of porin alterations on the susceptibility to ceftazidime/avibactam, and to describe a screening methodology for phenotypic detection of OXA-48-producing K. pneumoniae with disrupted porins. Antimicrobial susceptibility was tested by Microscan and Etest. The genomes of 81 OXA-48-producing K. pneumoniae were sequenced. MLST, detection of antimicrobial resistance genes, and analysis of ompK35 and ompK36 were performed in silico. Tridimensional structures of the OmpK36 variants were assessed. Receiver operating characteristics curves were built to visualize the performance ability of a disk diffusion assay using carbapenems and cefoxitin to detect OmpK36 functional alterations. A wide variety of OmpK36 alterations were detected in 17 OXA-48-producing K. pneumoniae isolates. All displayed a high-level meropenem resistance (MIC ≥ 8 mg/L), and some belonged to high-risk clones, such as ST15 and ST147. Alterations in ompK35 were also observed, but they did not correlate with high-level meropenem resistance. All isolates were susceptible to ceftazidime/avibactam and porin alterations did not affect the MICs of the latter combination. Cefoxitin together with ertapenem/meropenem low inhibition zone diameters (equal or lower than 16 mm) could strongly suggest alterations affecting OmpK36 in OXA-48-producing K. pneumoniae. OXA-48-producing K. pneumoniae with porin disruptions are a cause of concern; ceftazidime/avibactam showed good in vitro activity against them, so this combination could be positioned as the choice therapy to combat the infections caused by this difficult-to-treat isolates.

Sex differences in hospitalized adult patients with cellulitis: A prospective, multicenter study.

OBJECTIVES: Sex differences in adult cellulitis, a frequent cause of hospitalization, have not been analyzed. These differences were investigated in a large cellulitis series. METHODS: This was a prospective observational study of 606 Spanish hospitalized cellulitis patients. Different comorbidities, clinical, diagnostic, and treatment data were compared between the sexes. Multiple logistic regression modeling was performed to determine the variables independently associated with sex. RESULTS: Overall 606 adult cellulitis patients were enrolled; 314 (51.8%) were male and 292 (48.2%) were female. Females were older (mean age 68.8 vs 58.9 years, p < 0.0001), less likely to have prior wounds (p = 0.02), and more likely to have venous insufficiency (p = 0.0002) and edema/lymphedema (p = 0.0003) than males. The location of the infection differed between the sexes (p = 0.02). Males were more likely to have positive pus cultures (p = 0.0008), the causing agent identified (p = 0.04), and higher rates of Staphylococcus aureus infection (p = 0.04) and received longer antibiotic treatment (p = 0.03). Factors independently associated with female sex in the multivariate analysis were older age (p < 0.0001), prior cellulitis (p = 0.01), presence of edema/lymphedema as the predisposing factor (p = 0.004), negative versus positive pus culture (p = 0.0002), and location of cellulitis other than in the lower extremities (p = 0.035). CONCLUSIONS: Differences between male and female patients with cellulitis were age, recurrence, presence of edema/lymphedema, positivity of pus culture, and topography of the infection.

Ethambutol-resistant Mycobacterium kansasii cervical lymphadenitis in an immunocompetent adult patient: A case report and literature review.

Mycobacterium kansasii extrapulmonary infections are infrequent in immunocompetent adults. Rifampin (RIF), clarithromycin (CLR), isoniazid (INH) and ethambutol (EMB) are included in all the standard regimens against M.kansasii. We report a case of a healthy 65-year-old male farmer who presented with isolated right supraclavicular lymphadenopathy. The lymph node FNA showed acid-fast-bacilli and granulomatous inflammation. Quantiferon TB Gold test, HIV serology, and functional immunological studies were all negative or normal. He was put on a standard 4 drugs anti-tuberculous regimen that was switched to RIF + CLR+ INH after the Microbiology lab demonstrated an EMB-resistant Mycobacterium kansasii isotype I strain. The patient was cured after 12 months of therapy. This is the 6th reported case of M. kansasii extrapulmonary lymphadenitis in an immunocompetent adult and the 2nd showing EMB resistance in the world literature. Antimycobacterial regimens against M. kansasii, classically resistant to pyrazinamide (PZA) might also exclude EMB due to its increasing resistance in Europe. A 612 months therapy with at least 2 effective antimycobacterial drugs including RIF + CLR might be enough to treat extrapulmonary M. kansasii infections in immunocompetents.

Matrix metalloproteases and their tissue inhibitors in non-alcoholic liver fibrosis of human immunodeficiency virus-infected patients.

AIM: To investigate the relationships among diverse metalloproteases (MMPs) and their tissue inhibitors (TIMPs) and non-alcoholic liver fibrosis in human immunodeficiency virus (HIV)-infected patients. METHODS: Single nucleotide polymorphisms (SNPs) in MMPs, TNF-α and CCR5 genes, and serum levels of MMPs and TIMPs were determined in HIV-infected individuals with/out hepatitis C virus (HCV) coinfection. A total of 158 patients were included, 57 of whom were HCV-coinfected. All patients drank < 50 g ethanol/day. Diverse SNPs (MMP-1 -1607 1G/2G, MMP-8 -799C/T, MMP-9 -1562 C/T, MMP-13 -77A/G, TNF-α -308 G/A, CCR5-∆32), and serum levels of MMPs (2, 3, 8, 9 and 10) and TIMPs (1, 2 and 4) were assessed. Liver fibrosis was determined by transient elastometry, although other non-invasive markers of fibrosis were also considered. Significant liver fibrosis (F ≥ 2) was defined by a transient elastometry value ≥ 7.1 kPa. RESULTS: A total of 34 patients (21.5%) had liver fibrosis ≥ F2. MMP-2 and TIMP-2 serum levels were higher in patients with liver fibrosis ≥ F2 (P = 0.02 and P = 0.03, respectively) and correlated positively with transient elastometry values (P = 0.02 and P = 0.0009, respectively), whereas MMP-9 values were negatively correlated with transient elastometry measurements (P = 0.01). Multivariate analyses showed that high levels of MMP-2 (OR = 2.397; 95%CI: 1.191-4.827, P = 0.014) were independently associated with liver fibrosis ≥ F2 in the patients as a whole. MMP-2 (OR = 7.179; 95%CI: 1.210-42.581, P = 0.03) and male gender (OR = 10.040; 95%CI: 1.621-62.11, P = 0.013) were also independent predictors of fibrosis ≥ F2 in the HCV-infected subgroup. Likewise, MMP-2, TIMP-2 and MMP-9 were independently associated with transient elastometry values and other non-invasive markers of liver fibrosis. None of the six SNPs evaluated had any significant association with liver fibrosis ≥ F2. CONCLUSION: Certain MMPs and TIMPs, particularly MMP-2, seems to be associated with non-alcoholic liver fibrosis in HIV-infected patients with/without HCV coinfection.

Factors associated with liver fibrosis in intravenous drug users coinfected with HIV and HCV.

BACKGROUND: Reliable non-invasive methods for the evaluation of liver fibrosis are desirable, and the risk factors associated with fibrosis are not fully identified. METHODS: A cross-sectional study of a cohort of 805 HIV-HCV-coinfected patients with active HCV replication, most (95.2%) of whom were intravenous drug users, was conducted. Liver fibrosis was measured by transient elastometry with cutoff values of 7.2 kPa (significant fibrosis), 9.4 kPa (advanced fibrosis) and 14.0 kPa (cirrhosis), and by liver fibrosis indexes (LFI; APRI, Forns and FIB-4). Available liver biopsies were also evaluated. RESULTS: The prevalences of significant fibrosis, advanced fibrosis and cirrhosis were 55.8%, 38.4% and 23.5%, respectively. A number of parameters were associated both in the univariate and multivariate analyses with each of the diverse fibrosis groups; however, only six of them were predictive of all stages of fibrosis: heavy alcohol intake (odds ratio [OR] 3.37, 95% confidence interval [CI] 2.02-5.59; P < 0.001), duration of HCV infection (OR 1.13, 95% CI 1.07-1.19; P < 0.001), CDC category C3 (OR 1.80, 95% CI 1.07-3.02; P=0.026), anti-HCV treatment failure (OR 4.37, 95% CI 2.24-8.55; P < 0.001), thrombocytopaenia (OR 1.015, 95% CI 1.011-1.019; P < 0.001) and increased aspartate aminotransferase (1.006, 95% CI 1.0021-1.010; P = 0.004). Furthermore, 53%, 68% and 80% of patients with significant fibrosis, advanced fibrosis and cirrhosis, respectively, had increased measures on at least one of the LFI, with the Forns index being the most sensitive. Area under the receiver operating characteristic curves of elastometry to predict histological fibrosis was 0.83 (95% CI 0.76-0.90), 0.89 (95% CI 0.83-0.95) and 0.87 (95% CI 0.80-0.94) for Metavir score ≥ F2, ≥ F3 and F4, respectively. CONCLUSIONS: Elastometry constitutes a useful tool in the diagnosis and follow-up of HIV-HCV-coinfected patients. Fibrosis is associated with diverse factors, some of them treatable or preventable, which need to be addressed considering the high prevalence and course of fibrosis in these patients.

The MMP1 (-16071G/2G) single nucleotide polymorphism associates with the HAART-related lipodystrophic syndrome.

OBJECTIVE: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in extracellular matrix remodelling and adipocyte differentiation and are inhibited by antiretrovirals. MMPs and TIMPs and their single nucleotide polymorphisms (SNPs) might contribute to the HAART-related lipodystrophic syndrome pathogenesis. DESIGN AND SETTING: Cross-sectional study in a university-based outpatient clinic. PATIENTS AND METHODS: Two hundred and sixteen HIV-infected patients on extended HAART were studied. Serum MMPs (1, 2, 3, 8, 9, 10, 13) and TIMPs (1, 2, 4) were measured by ELISA microarrays. MMP1 (-16071G/2G) SNP was also genotyped. Lipodystrophic syndrome was diagnosed by a clinical scale validated by fat dual energy X-ray absorptiometry. RESULTS: Eighty-two patients (38.0%) showed lipodystrophic syndrome, mostly lipoatrophy. The 2G/2G MMP1 SNP genotype was more frequent among lipodystrophic syndrome patients (41.3 vs. 20.5%, odds ratio, 2.73; 95% confidence interval, 1.41-5.29; χ² = 9.62, P = 0.002 for HIV-infected patients with and without lipodystrophic syndrome respectively). Carriers of this genotype had higher serum levels of MMP1 compared with those with the 1G/1G (P = 0.02). Higher MMP1 (P = 0.022) and lower TIMP4 (P = 0.038) serum levels were observed while comparing HIV patients with and without lipodystrophic syndrome. MMP1 2G carriage (P = 0.0008), TIMP4 lower serum levels (P = 0.02), treatment with stavudine (P < 0.0001), treatment with zidovudine (P = 0.006) and absence of hepatitis C virus coinfection (P = 0.002) were associated with lipodystrophic syndrome by logistic regression. CONCLUSION: MMP1 SNP, which induced increased serum levels of this protein, was associated with lipodystrophic syndrome.