Combination antibiotic treatment versus monotherapy for multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter infections: a systematic review.

Controversy surrounds combination treatment or monotherapy against multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) Acinetobacter infections in clinical practice. We searched the PubMed and Scopus databases for studies reporting on the clinical outcomes of patients infected with MDR, XDR, and PDR Acinetobacter spp. with regard to the administered intravenous antibiotic treatment. Twelve studies reporting on 1,040 patients suffering from 1,044 infectious episodes of MDR Acinetobacter spp. were included. The overall mortality between studies varied from 28.6 to 70 %; from 25 to 100 % in the monotherapy arm and from 27 to 57.1 % in the combination arm. Combination treatment was superior to monotherapy in three studies, where carbapenem with ampicillin/sulbactam (mortality 30.8 %, p = 0.012), carbapenem with colistin (mortality 23 %, p = 0.009), and combinations of colistin with rifampicin, sulbactam with aminoglycosides, tigecycline with colistin and rifampicin, and tigecycline with rifampicin and amikacin (mortality 27 %, p < 0.05) were used against MDR Acinetobacter spp. resistant at least to carbapenems. The benefit was not validated in the remaining studies. Clinical success varied from 42.4 to 76.9 % and microbiological eradication varied from 32.7 to 67.3 %. Adverse events referred mainly to polymixins nephrotoxicity that varied from 19 to 50 %. The emergence of resistance was noted with tigecycline regimens in off-label uses in three studies. The available data preclude a firm recommendation with regard to combination treatment or monotherapy. For the time being, combination treatment may be preferred for severely ill patients. We urge for randomized controlled trials examining the optimal treatment of infections due to MDR, XDR, and PDR Acinetobacter spp.

Evaluation of a pro-active strategy for managing tuberculosis-HIV co-infection in a UK tertiary care setting.

Management of tuberculosis (TB)-HIV co-infection is complicated by interactions between the diseases and their therapies. We developed and evaluated a strategy to (i) treat co-infected patients in a single co-infection clinic, (ii) maximize use of first-line drugs, (iii) delay antiretroviral therapy (ART) until two months post-TB treatment except in severe immunosuppression, (iv) commence efavirenz at 600 mg daily with therapeutic drug monitoring (TDM) and (v) target treatment completion. We conducted a prospective cohort review over 5.5 years in a UK tertiary referral center where 56 HIV-positive patients treated for TB were followed-up for a median 30 months. Main outcome measures were treatment completion, adverse events, immune reconstitution inflammatory syndrome, immunological and virological parameters, and TDM for efavirenz. Treatment completion rates were 88% (49/56); four patients were lost to local follow-up and three (5.4%) died during treatment; no deaths were TB-related. Adverse events were common (55%), but caused no treatment interruptions. Standard doses (600 mg daily) of efavirenz with rifampicin achieved or exceeded therapeutic levels in 25/28 (89%). This study supports combined management for TB-HIV co-infected patients. Delaying ART to two months post-TB treatment did not seem to result in poor clinical outcomes in this well-resourced context. Although efavirenz 600 mg daily usually achieved satisfactory levels, TDM is recommended.

A case of recurrent benign lymphocytic (Mollaret's) meningitis and review of the literature.

Mollaret's meningitis is a rare form of benign recurrent aseptic meningitis first described in 1944. We report a case of Mollaret's meningitis due to Herpes Simplex Virus type 2 (HSV2), diagnosed with Polymerase Chain Reaction (PCR) implementation in the Cerebrospinal fluid (CSF) of the patient and treated successfully with acyclovir. To our knowledge, this is the first case of Mollaret's meningitis reported in Greece. We reviewed the literature since PCR has become widely available. Herpes Simplex Virus type 2 has been the most commonly identified causative agent of Mollaret's meningitis.

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK.

The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

L-DOPA decarboxylase association with membranes in mouse brain.

This work presents evidence on the association of active DDC molecules with membranes in mammalian brain. L-DOPA decarboxylase (DDC) is generally considered to be a cytosolic enzyme. Membrane-associated DDC was detected by immunoblotting and enzymatic assay experiments. DDC activity and immunoreactivity could be partially extracted from mammalian brain membranes by detergent. Fractionation of membranes by temperature-induced phase separation in Triton X-114, resulted in the recovery of membrane-associated DDC in separation phases where integral and hydrophobic membrane proteins separate. Treatment of membranes with phosphatidylinositol-specific phospholipase C or proteinase K, did not elute membrane-associated DDC activity, suggesting that a population of DDC molecules exist embedded within membranes. The elucidation of the functional significance of the enzyme's association with membranes could provide us with new information leading to the better understanding of the biological pathways that DDC is involved in.