Objective To compare the efficacy of pain control and opioid consumption between patients who receive opioid as primary analgesic therapy and those who receive ibuprofen. Study Design Prospective randomized trial. Setting Tertiary care academic hospital. Subject and Methods Adult patients undergoing outpatient otolaryngology surgery were assigned to take hydrocodone/acetaminophen or ibuprofen for postoperative analgesia. Patient-recorded pain scores and analgesic consumption were analyzed. Results Out of 185 recruits, 108 (58%) completed responses. Fifty-six patients (52%) received opioid medication for primary analgesic treatment versus 52 (48%) who received ibuprofen. There was no difference in reported pain scores between the treatment groups. Those who received ibuprofen as primary therapy reported a significantly lower consumption of opioid medication at 2.04 tablets/pills (95% CI, 0.9-3.1) versus 4.86 (3.6-6.1; P = .001). Based on multivariate analysis, male sex and older age exhibited lower reported pain scores, while older age and use of ibuprofen as primary therapy exhibited lower opioid requirements. Conclusion For postoperative pain management in outpatient otolaryngology procedures, ibuprofen as primary therapy can provide equally effective pain control as compared with hydrocodone/acetaminophen while decreasing overall opioid requirement. Prescription pill counts are further described to help guide physician practices in the era of an opioid epidemic.

Inflammation-mediated reactive molecules can damage DNA by oxidation and chlorination. The biological consequences of this damage are as yet incompletely understood. In this paper, we have constructed oligonucleotides containing 5-chlorouracil (ClU), one of the known inflammation damage products. The thermodynamic stability, base pairing configuration and duplex conformation of oligonucleotides containing ClU paired opposite adenine have been examined. NMR spectra reveal that the ClU-A base pair adopts a geometry similar to that of the T-A base pair, and the ClU-A containing duplex adopts a normal B-form conformation. The linewidth of the imino proton of the ClU residue is substantially greater than that of the corresponding T imino proton; however, this difference is not attributed to a reduced thermal or thermodynamic stability or to increased proton exchange with solvent. While the NMR studies reveal increased chemical exchange for the ClU imino proton of the ClU-A base pair, the ClU residue is not a target for removal by the Escherichia coli mispaired uracil glycosylase, which senses damage-related helix instability. The results of this study are consistent with previous reports indicating that the DNA of replicating cells can tolerate substantial substitution with CIU. The fraudulent, pseudo-Watson-Crick ClU-A base pair is sufficiently stable to avoid glycosylase removal and, therefore, might constitute a persistent form of cellular DNA damage.

Cytosine methylation patterns are essential for the proper control of gene expression in higher vertebrates. Although alterations in methylation patterns are frequently observed in human tumors, neither the mechanisms for establishing methylation patterns during normal development nor the mechanisms leading to pathological alterations of methylation patterns are currently known. While epidemiological studies have implicated inflammation in cancer etiology, a mechanistic link has yet to be established. Investigations of inflammation-mediated DNA damage may have provided important new insights. Our in vitro studies revealed that the inflammation-mediated DNA damage product, 5-chlorocytosine, could direct fraudulent methylation of previously unmethylated CpG sites. The purpose of this study was to recapitulate our in vitro findings by introducing 5-chlorocytosine residues into the DNA of replicating mammalian cells and to examine its impact on gene expression and cytosine methylation patterns. CHO-K1 cells hemizygous for the hprt gene were electroporated with the triphosphates of cytosine [2'-deoxycytidine-5'-triphosphate (dCTP)], 5-methylcytosine [5-methyl-2'-deoxycytidine-5'-triphosphate (MedCTP)] and 5'-chloro-2'-deoxycytidine-5'-triphosphate (CldCTP), and then selected with 6-thioguanine for silencing the hprt gene. Both modified nucleotides, MedCTP and CldCTP, but not unmodified dCTP, silenced hprt gene expression. Subsequent bisulfite pyrosequencing of CpG sites within the hprt promoter region of the selected cells confirmed hypermethylation, although global methylation levels as measured by gas chromatography-mass spectrometry did not change. Modified nucleotide-induced gene silencing could be reversed with 5-aza-2'-deoxycytidine indicating an epigenetic rather than mutagenic alteration. These results provide further evidence that the inflammation damage product 5-chlorocytosine could be a link between inflammation and cancer development.

Hypochlorous acid (HOCl) from activated neutrophils at sites of inflammation can react with and damage biological molecules including nucleic acids. The reaction of HOCl with cytosine analogs can generate multiple products including 5-chlorouracil (ClU). In this paper, we have constructed oligonucleotides containing ClU paired opposite guanine (ClU-G). Melting studies indicate that oligonucleotide duplexes containing the ClU-G mispair are substantially less stable than those containing a ClU-A base pair. The melting temperature of the ClU-G mispair is not experimentally distinguishable from G-T. NMR studies indicate that the ClU-G base pair adopts a wobble geometry at neutral pH, similar to a T-G mispair. The exchangeable protons of the ClU-G mispair broaden rapidly with increasing temperature, indicating that the ClU-G mispair is less stable and opens more easily than the surrounding adjacent base pairs. Unlike the ClU-A base pair studied previously (Biochemistry 48, 7539–46, 2009), the ClU-G mispair undergoes a pH-dependent structural change, assuming an ionized base pair configuration that approximates a Watson-Crick base pair at higher pH. Ionization of ClU in a DNA template could promote mispair formation and mutation, in accord with previous studies on other 5-halouracil analogs. The electron-withdrawing 5-chloro substituent facilities ionization of the ClU N3 proton, promoting mispair formation, but it also renders the glycosidic bond susceptible to base cleavage by DNA repair glycosylases.

Neurosurgical procedures inevitably produce intraoperative hemorrhage. The subsequent entry of blood into the brain parenchyma results in the release of large amounts of thrombin, a known contributor to perihematomal edema formation and apoptosis after brain injury. The present study seeks to test 1) the effect of surgically induced brain injury (SBI) on thrombin activity, expression of thrombin’s receptor PAR-1, and PAR-1 mediated apoptosis; 2) the effect of thrombin inhibition by argatroban and PAR-1 inhibition by SCH79797 on the development of secondary brain injury in the SBI model on rats. A total of 88 Sprague-Dawley male rats were randomly divided into sham, vehicle-, argatroban-, or SCH79797-treated groups. SBI involved partial resection of the right frontal lobe under inhalation isoflurane anesthesia. Sham-operated animals received only craniotomy. Thrombin activity, brain water content, and neurological deficits were measured at 24 hours following SBI. Involvement of the Ask1/JNK pathway in PAR-1-induced post-SBI apoptosis was characterized by using Ask1 or JNK inhibitors. We observed that SBI increased thrombin activity, yet failed to demonstrate any effect on PAR-1 expression. Argatroban and SCH79797 reduced SBI-induced brain edema and neurological deficits in a dose-dependent manner. SBI-induced apoptosis seemed mediated by the PAR-1/Ask1/JNK pathways. Administration of SCH79797 ameliorated the apoptosis following SBI. Our finding indicate that PAR-1 antagonist protects against secondary brain injury after SBI by decreasing both brain edema and apoptosis by inactivating PAR-1/Ask1/JNK pathway. The anti-apoptotic effect of PAR-1 antagonists may provide a promising path for therapy following SBI.