Comparison of Spinal Cord Stimulation Outcomes Between Preoperative Opioid Users and Nonusers: A Cohort Study of 467 Patients

ObjectivesSpinal cord stimulation (SCS) is a surgical treatment modality reserved for a subset of patients with neuropathic pain in which conventional pharmacologic treatment has proven insufficient. Previous studies have suggested a possible negative relationship between opioid use at referral and subsequent success of SCS therapy. The aim of this cohort study was to investigate whether preoperative opioid use was associated with inferior SCS outcomes.Materials and MethodsData were obtained from the Danish Neurizon Neuromodulation Database and comprised preoperative registrations of analgesic use, postoperative Patients’ Global Impression of Change (PGIC) ratings, pre- and postoperative pain intensity scores (Numeric Rating Scale), and detailed surgical data. Patients were dichotomized according to preoperative opioid use (users vs nonusers) with subsequent assessment of the latest PGIC rating, reduction in pain intensity, and current treatment status (implanted/explanted). In addition, daily preoperative opioid dosages were quantified in oral morphine equivalents (OME) and correlated to the treatment outcomes.ResultsA total of 467 patients were included; 296 consumed opioids before SCS implantation (median 80 OME/d). Preoperative opioid use was not associated with the latest PGIC rating, reduction in pain intensity (30% or 50%), or risk of undergoing explantation (median follow-up = 3.0 years). Likewise, preoperative median OME per day of opioid users was not correlated with any of the defined outcomes.ConclusionsPreoperative opioid usage did not predict the outcome of SCS therapy in a large cohort of patients permanently implanted with an SCS system. The results do not support withholding otherwise well-indicated SCS therapy in patients with chronic neuropathic pain conditions based merely on preoperative opioid usage.     

The Th1 immune response against HIV-1 Gag p24-derived peptides in mice expressing HLA-A02.01 and HLA-DR1

Using HLA-DR1-transgenic H-2 class II knockout mice, we identified two new HLA-DR1-restricted HIV-1 Gag p24-derived epitopes (Gag(321-340 )and Gag(331-350)) and confirmed the immunogenicity of seven that have been previously described. The human relevance was confirmed for the two new ones (Gag(321-340 )and Gag(331-350)) assaying peripheral blood mononuclear cells from HLA-DR1(+) HIV-1-infected long-term asymptomatic subjects and showing that Gag(331-350) could prime CD4(+) T cells from two HLA-DR1(+) HIV-1 seronegative donors in vitro. Seven of these epitopes, structurally conserved among HIV-1 clade B isolates, were selected for a comparative evaluation of their Th1 helper potential by immunizing HLA-A02.01/HLA-DR1-transgenic, H-2 class I/class II knockout mice with recombinant mouse invariant chain constructs in which each helper epitope was inserted in association with two reporter HIV-1-derived HLA-A02.01-restricted CD8(+) T cell epitopes. A T helper effect was demonstrated in all cases, and was particularly strong with epitopes Gag(301-320),Gag(321-340 )and Gag(271-290), which should, therefore, be considered in the design of new vaccines.     

Reversal of resistance in microorganisms by help of non-antibiotics

Intracellular efflux pumps have been largely the research focus in multidrug-resistant (MDR) Gram-positive and Gram-negative microorganisms and parasites including cancers. However, drug efflux mechanisms other than pumps per se have been observed, supported by the effects of isomeric, non-antibiotic depressant (DPR), phenothiazines and thixenes, and antidepressant (ADPR) phenylpiperidine neurotropic drugs, alone or in combination with classical antimicrobials on MDR Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes and Streptococcus pneumoniae. Of the non-antibiotics we investigated, the DPR l-thioridazine, trans-clopenthixol and isomers of phenylpiperidines NNC 20-4962 (isomer of femoxetine) and NNC 20-7052 (isomer of paroxetine) were potent antimicrobials with the least neurotropic activity, pointing to a possible general isomeric structure-activity relationship. These compounds may be regarded as new efflux inhibitors. Moreover, these isomers have considerably reduced, in some cases absent, neurotropism and reduced mammalian toxicity. This may alleviate concerns about adverse effects and therapeutic safety for infected patients in life-threatening situations where the non-antibiotic dosage would be in the lower, non-chronic dosage ranges generally prescribed for individuals with mild mental health problems. The results point to the prokaryotic and eukaryotic microorganisms' phospholipid/protein domain involvement of the cationic, amphiphilic, non-antibiotic DPR and ADPR, with the phospholipids being the initial sites attracting and concentrating the neurotropes to induce a form of suspended animation, followed by gross changes of cell wall and membrane structure, and thereby potentiating their destructive or immobilizing effects on various as yet only hinted at resistance and efflux mechanisms. Combination of appropriate isomeric non-antibiotic DPR and ADPR of low neurotropism and toxicity with conventional and classical antimicrobials promises early, new therapeutic strategies salutary against microbial resistance, resistance development, pathogenicity and virulence.     

Synthesis, physicochemical properties, antimicrobial and antioxidant studies of pyrazoline derivatives bearing a pyridyl moiety

A series of new pyrazoline compounds bearing a pyridyl moiety (4a–i) were synthesized by condensing appropriate chalcones with hydrazine hydrate and tested for antimicrobial and antioxidant activities. According to in vitro antimicrobial activity against Bacillus subtilis, Staphylococcus epidermidis, Proteus vulgaris, Pseudomonas aeruginosa, Aspergillus niger and Penicillium chrysogenum and antioxidant activity by DPPH method, the compounds 4a, 4d, 4i and 4e, 4f, 4h showed maximum antimicrobial and antioxidant activities, respectively. Physiochemical properties and Lipinski’s ‘Rule of Five’ analysis predicted higher intrinsic quality of the synthesized compounds and revealed that these compounds have good bioavailability and druglikeness properties.     

Myocardial expression of CC- and CXC-chemokines and their receptors in human end-stage heart failure

OBJECTIVES: Chemokines regulate several biological processes, such as chemotaxis, collagen turnover, angiogenesis and apoptosis. Based on the persistent immune activation with elevated circulating levels of chemokines in patients with congestive heart failure (CHF), we have hypothesised a pathogenic role for chemokines in the development of CHF. The objective of this study was to examine mRNA levels and cellular localisation of chemokines and chemokine receptors in human CHF. METHODS: We examined explanted hearts from ten patients with end-stage heart failure (all chambers) and in ten organ donors using an RNase protection assays and immunohistochemical techniques. RESULTS: Our main findings were: (i) expression of eight chemokine and nine chemokine receptor genes in both failing and nonfailing myocardium, (ii) particularly high mRNA levels of monocyte chemoattractant protein (MCP)-1 and CXC-chemokine receptor 4 (CXCR4), in both chronic failing and nonfailing myocardium, (iii) decreased mRNA levels of MCP-1 and interleukin (IL)-8 in the failing left ventricles compared to failing left atria, (iv) decreased chemokine (e.g., MCP-1 and IL-8) and increased chemokine receptor (e.g., CCR2, CXCR1) mRNA levels in failing left ventricles and failing left atria compared to corresponding chambers in the nonfailing hearts and (v) immunolocalisation of MCP-1, IL-8 and CXCR4 to cardiomyocytes. CONCLUSION: The present study demonstrates for the first time chemokine and chemokine receptor gene expression and protein localisation in the human myocardium, introducing a new family of mediators with potentially important effects on the myocardium. The observation of chemokine dysregulation in human end-stage heart failure may represent a previously unknown mechanism involved in progression of chronic heart failure.